Psychology Department, Institute of Neuroscience ISNR 2010, Denver, Sep. 29-Oct. 3 WS 8: ERP Protocols in Clinical Assessment Part 1 Elena Labkovsky, Ph.D. Rosenfeld Lab Psychology Department, Institute of Neuroscience

WS 8: ERP Protocols in Clinical Assessment What we will learn: Basics of ERP method: ERP origins, physiology, modalities, major ERP components, and principles of ERP protocol design (45-60 min). ERP Protocol: Principles for development of Stimuli Presentation Protocol or “Task” (60 min). Applications: ERP Method and demonstration of different ERP protocols in clinical applications (60-75 min).

WS 8: ERP Protocols in Clinical Assessment

WS 8: ERP Protocols in Clinical Assessment What (and Why) we will NOT learn : Scalp preparation; Electrode placement (International10/20 system); EEG recording montages; EEG recording equipment maintenance Why??? Because it is all the same as with continues EEG recording

WS 8: ERP Protocols in Clinical Assessment Cognitive processing involves activation of multiple generators in the brain. Event-related potentials represent these activations of the brain systems.

Event-Related Potentials (ERPs)

WS 8: ERP Protocols in Clinical Assessment Event Related Potentials (ERPs) is a measure of brain activity, derived from EEG recording. EEG represents spontaneous brain activity, but ERP is generated as a response to specific stimuli, and is an average of a number of samples. ERPs are time-locked measures of brain electrical activity and represent a distinct phase of cortical processing. ERPs are dependent on both physical and psychological characteristics of stimuli. ERPs occurring independently of external stimuli are called endogenous (they are produced by internal events). ERPs produced as a reaction to specific external events are called exogenous potentials.

WS 8: ERP Protocols in Clinical Assessment Since the 1940s, the time of ERP discovery, the ERP method became particularly accessible to and widely used in noninvasive study and clinical assessment. The development of averagers, digital converters, and computers promoted a rapid expansion in the application of ERP method in both neuroscience research and clinical practice. During the last 10 years the number of published journal articles and books (based on the use of ERP method) multiplied more than 50 times (from 581 in 1999 to 26,365 in 2009) There were 24,456 journal articles and 2,480 books (based on the use of ERP method) published during last 10 years.

WS 8: ERP Protocols in Clinical Assessment

WS 8: ERP Protocols in Clinical Assessment ERP Method: WHY………….. WHY ERP Method? Because ERP is a noninvasive, precise, and reliable clinical and research tool; ERP method allows not only recording the brainwaves but also reveal how these brain waves are related to psychological states and conditions. ERPs reflect perceptual and cognitive processing and can be used for differential diagnosis of psychological, psychiatric, and neurological conditions

WS 8: ERP Protocols in Clinical Assessment ERP Method: What for? ERP-based Clinical Assessment: To monitor developmental progress; To ensure a baseline pattern for a person’s brain activity related to specific cognitive tasks; To measure an impact of a brain injury (after sport trauma, car or other traumatic accident, food/chemical poisoning, virus infection, radio-active exposure, chemo/radio therapy, etc.) to brain functioning; To check up on the current brain functionality and detect any brain functioning abnormality; To assess a treatment effect; To provide an early diagnosis of psychological/neuropsychological conditions and genetic pervasive and degenerative diseases related to nervous system functioning.

ERP Method: What for…………. Psychological/Cognitive Conditions , such as: AD/HD (P300); Learning Disorders/LD (P300, N400….); Depression (CNV, MMN, P300); Panic Disorders (CNV, MMN, P300, N400); Traumatic Brain Injury/TBI (P300); Post Traumatic Amnesia /PTA (P300); Mild Cognitive Impairment /MCI (N200/MMN, P300, SW) Minimally Conscious State (P300); Malingering (P300); Personality Disorders /schizoid, antisocial, and borderline/ (P300).

ERP Method: What for…………. Neurological conditions, such as: Multiple sclerosis; CNS Degenerative Disease; Huntington’s Chorea; Parkinson’s Disease; Alzheimer’s Disease; Progressive Supranuclear Palsy; Human Immunodeficiency Virus (HIV). Psychiatric conditions, such as: Schizophrenia (N200, P300, CNV, MMN); Anxiety Neurosis (CNV), etc.

ERP Method: What for…………. Forensic Investigations: Detection of Deception (P300); Witness testimony (P300); Forensic neurocognitive evaluation, etc. Research: Cognitive Development; Cognitive Processing; Aging, etc.

ERP Method: What for…………. The 3Ds of ERP Method: Diagnose (a problem); Discover (brain mechanisms of cognitive processing); Discriminate (brain reactions to events).

WS 8: ERP Protocols in Clinical Assessment

How? ERP Method: How…………. Recording of EEG with stimuli presentation and averaging of temporal epochs associated with presented stimuli; Thus, three systems are involved: Stimulus Presentation System; Data Acquisition System; and Data Analysis System.

WS 8: ERP Protocols in Clinical Assessment The ERP signal is expressed as a series of positive and negative deflections distributed across time. They are called “ERP Components.” Often ERP components are defined and named on the basis of their polarity (“N”- for negative polarity and “P”-for positive polarity) and their characteristic latency (ex: P300- positive, around 300ms; N400- negative, around 400ms).

N100 (or N1)

N100 (or N1) Name: N100 (or N1), exogenous (stimulus-dependent) negative component related to attention (Hillyard, Hink, Schwent, & Picton, 1973); Latency and Localization: it peaks in adults between 80 and 120 ms (auditory) and 100-150 ms (visually) post-stimulus and is distributed mostly over the fronto- central region of the scalp; Paradigm: It can be elicited by any unpredictable stimulus in the absence of task demands. Examples: Odd-ball paradigm with 2 stimuli (frequent “standard” and rare “target”). Odd-ball with 3 stimuli (frequent “standard”, rare “target” and rare “novel”). The N100 is weaker when stimuli are repetitive, and stronger when they are random. When subjects are allowed to control stimuli, using a switch, the N100 may even disappear; Application: Prediction of recovery for patients in coma or assessing the optimal level of sedation in intensive critical care. ADHD, Dyslexia, schizophrenia (reduced N1), migraine (increased N1), developmental assessment, Down syndrome.

N100 (or N1)

Name: Negative Difference (Nd) Name: Negative Difference (Nd) is related to attention (Hillyard, Hink, Schwent, & Picton, 1973) Latency and Localization: around 90-130ms, the brain substrates appear to be primary auditory, visual, and somatosensory cortex; Paradigm: Stimuli (visual or auditory) are presented rapidly and periodically an aspect of the stimulus varies. Examples: (same as for N100); Example: Tones are presented to both ears. Subject is instructed to attend to only one ear. Tone deviation in the “attended” ear elicits larger ERP amplitude compared to “unattended” ear. The difference is largest at 90-130ms for “Early” Nd and about 300-400ms for “Late” Nd; Application: developmental assessment, early diagnosis of pathology (schizophrenia).

ERP components (N1, Nde, and Ndl): Scalp distributions Name: Negative Difference (Nd) ERP components (N1, Nde, and Ndl): Scalp distributions These components were produced during selective attention task. N1: elicited by tones in nonattended channel; Nde: obtained by subtracting the ERPs in nonattended channel from the ERP produced by the same stimuli in the attended channel. Ndl obtained by subtraction within 300-400ms (adopted from “Event-Related Brain Potentials. Basic Issues and Applications.” Eds. Rohrbaugh, J., Parasuraman, R., and Jhnson, R.

P200 (or P2)

Application: developmental assessment. P200 (or P2) Name: P200 (P2); Latency and Localization: it peaks in between 150 -275ms post- stimulus and is distributed mostly over the centro-frontal and the parieto- occipital regions of the scalp (maximal around the vertex); Paradigm: It is elicited by any repetitive and /or rare stimuli; It is larger for “Target” stimuli and increases in amplitude even more when Targets are rare. The anterior P200 component occur for fairly simple stimuli. The posterior P200 is often difficult to distinguish from the overlapping N1, N2, and P3 components. Application: developmental assessment.

Developmental Changes in P100, N100, and P200 ERP Components P200 (or P2) Developmental Changes in P100, N100, and P200 ERP Components Thick traces are from infants, children, and adolescents; Thin traces are from adults; The traditional known N100-P200 response does not have an adults morphology until 10-16 years of age; ERP were elicited by the: “da” sound in 1mo-2yo “me” sound in 4-18 yo “dog” sound in adults (adopted from “Event-Related Brain Potentials. Basic Issues and Applications.” Eds. Rohrbaugh, J., Parasuraman, R., and Jhnson, R.

N200 (or N2)

N200 (or N2) Name: N200 (N2). There are many clearly different components in 200ms time range – the N2 family; Latency and Localization: These components peak from 200 to 350vs post-stimulus and are distributed over the fronto-central regions (for auditory stimuli) and Parietal regions (for visual stimuli); Paradigm: The basic N200 component can be elicited by repetitive nontarget stimuli. Rare deviant stimuli elicit larger N200. The N200 component is, especially in Go/NoGo tasks, linked to inhibitory processes as response inhibition with a strong negative amplitude for the NoGo part . Application: ADHD, Depression, Mild Cognitive Impairment, Schizophrenia, Developmental Assessment, TBI, etc.

Mismatch Negativity (MMN) Name: Mismatch Negativity (MMN) (Naatanen, 1982; Loveless, 1983) MMN is an endogenous component representing internal processes in contrast to N1 (exogenous, sensory component). MMN reflects stimuli categorization process. Paradigm: Infrequent (20%) stimuli (visual or auditory) presented along with frequent (80%) stimuli – an “odd-ball” paradigm. Large deviances elicit MMN at earlier latencies. Latency and Localization: MMN latencies vary from 120-220ms (auditory) to 150-250ms (visual). The auditory MMN is a fronto-central negative potential (sources in the primary and non-primary auditory cortex). Example: A subject is presented with a sequence of sounds: “s s s s s s s d s s s s d...,” the “d” is the deviant or oddball stimulus, and will elicit an MMN response. MMN occurs even if the subject is not consciously paying attention to the stimuli. Application: Learning difficulties: Assessment of neurolinguistic perception (testing ability to distinguish between certain kinds of sounds); phonological and syntactic processing; diagnosis of schizophrenia and depression. “Mismatch Negativity”

Mismatch Negativity (MMN)

P300 (or P3)

P300 (or P3) Name: P300 - best-studied, both in healthy subjects and mental disorders patients (Sutton, Braren, & Zubin, 1965). Paradigm: a series of stimuli are presented. There are two types of stimuli: rare and frequent (“odd-ball task”). Subjects are instructed to respond by pressing a button to or counting of the rare stimulus. Latency and Localization: ~300-900ms, most profound at frontal- central regions Fz and Cz (for P3a- “novelty” component) and parietal sites (for P3b elicited by rare and meaningful stimuli). Example: ”Visual P300” ,“Faces” Application: abnormally reduced P300 amplitude is shown to be a reliable marker for schizophrenia, loosening of associations (similar to observed in schizophrenia patients), dementia, substance abuse, depression, anxiety disorder, posttraumatic stress disorder and personality disorders (schizoid, antisocial, and borderline).

P300 (or P3)

P300 (or P3) P300-Protocol Example: 3 Stimuli (Odd-ball) P300-based protocol (with acoustic stimuli) for detection of malingering/deception Protocol Description: Audio Stimuli Recognition P300-based protocol, contains three types of stimuli: A “Probe” (P--a relevant to the subject item (his/her Last Name), “Irrelevant” (I—a last name, NOT relevant to the subject), and a “Target” (T, an item with “assigned significance”). The stimuli are presented to subject through headphones. There are 7 different stimuli (last names) included in the protocol: five Irrelevant names, one Probe, and one Target. Each of the names repeats 30 times in a single test run. Subjects respond to all Irrelevants and the Probe with a left button on a two- button response box. They are instructed to press a RIGHT button when they hear a “Target” name.

P300 (or P3), Example: Method: “elab”

P300 (or P3), Example:

P300 (or P3), Example: Conclusions: The study confirmed that P300 component can effectively serve as an indicator of feigning/malingering in audio-stimuli (words) ERP-based protocol:  P300 amplitude significantly increases when presented audio information is recognized (even when a person denies it) compared to unrecognized stimuli.

N400 Name: N400 (first described by Kutas and Hillyard in 1980) Paradigm: In 25% of sentences read by subjects, the ending was moderately or strongly inappropriate. Latency and Localization: around 400ms (300-500ms) after the unexpected stimulus, distributed over central-parietal sites. Example: Moderately inappropriate: “He took a sip from a waterfall”. Strongly inappropriate: “He took a sip from a transmitter”. Application: Developmental assessment, linguistic processing, etc. Reduced N400 amplitude is observed in patients with schizophrenia and depression.

Contingent Negative Variation (CNV) Name: Contingent Negative Variation (CNV) (first described by Walter and colleagues in 1964). Paradigm: There are two stimuli in each trial (S1 and S2). The first stimulus (S1) is a “warning signal” and the second one (S2) follows S1 and requires a response from a subject. There was a steady, relatively long lasting, negative shift (CNV) observed between S1 and S2, reaching its peak at the time of S2 onset. Latency and localization: ~400-1000 ms (between S1 and S2), max at vertex (Cz). Example: In the original version a warning click (S1) was first presented, followed by a flashing light (S2). The subject was instructed to press a button in response to S2 (light). Application: Numerous studies have confirmed the applicability of CNV on the diagnosis of dementia, Parkinson's disease, epilepsy, anxiety states, chronic pains, including migraine, and schizophrenia (for example: reduced CNV amplitude is observed in patients with schizophrenia and depression).

Contingent Negative Variation (CNV)

Contingent Negative Variation (CNV) VCPT Task (from Psytask)

Contingent Negative Variation (CNV)

Contingent Negative Variation (CNV)

WS 8: ERP Protocols in Clinical Assessment

WS 8: ERP Protocols in Clinical Assessment Task Construction

WS 8: ERP Protocols in Clinical Assessment Task Construction What is needed for collecting ERP data: 1. Stimulus Presentation System; 2. Data Acquisition System; 3. Data Analysis System.

WS 8: ERP Protocols in Clinical Assessment Task Construction What is needed for collecting ERP data: 1. Stimuli Presentation System. 2. Data Acquisition System; 3. Data Analysis System.

WS 8: ERP Protocols in Clinical Assessment Task Construction Software for developing a stimuli presentation protocol and delivering stimuli to a patient/subject. Computer for presenting stimuli. Stimuli Presentation Protocol or “Task.”

WS 8: ERP Protocols in Clinical Assessment Task Construction Stimuli Presentation System

WS 8: ERP Protocols in Clinical Assessment Task Construction Task Construction and Stimuli Presentation Software: “Psytask”, http://www.mitsar-medical.com (compatible with WinEEG); “Presentation” , http://www.neurobs.com (compatible with WinEEG); “E-Prime”, http://www.pstnet.com (compatible with WinEEG).

WS 8: ERP Protocols in Clinical Assessment Task Construction Basic Trial Structure

WS 8: ERP Protocols in Clinical Assessment Task Construction: EXAMPLE Questions to be answered before constructing stimuli presentation protocol: What are the stimuli (images, sounds, etc.)? Stimuli categories (Probe, Irrelevant, Target, Nontarget, etc); Preparation of the stimuli (image/acoustic files); Stimuli ratio (stimuli probability issue); Structure of a trial (simple or complex); Stimuli exposition time; Trial duration; Inter-trial (or inter-stimuli) interval; Total number of trials; Randomization.

Task Construction and Stimuli Presentation: 1. Stimuli. What are the stimuli? Acoustic: tones/beeps words Visual: images

2. Stimuli categories (Probe, Irrelevant, Target, Nontarget, etc. Task Construction and Stimuli Presentation: 2. Number of Probe(s) and Irrelevants 2. Stimuli categories (Probe, Irrelevant, Target, Nontarget, etc. Odd-ball paradigm: In our “Detection of Deception” studies we utilize one Probe, one Target and 4 to 6 Irrelevant stimuli. In our most recent “Acoustic” study with last names: five Irrelevant names, one Probe, and one Target.

“Target/Nontarget” response box Task Construction and Stimuli Presentation: 2. Number of Probe(s) and Irrelevants 2. Stimuli categories (Probe, Irrelevant, Target, Nontarget) (continues): Complex trial Protocol (CTP): Complex Trial Protocol (CTP) is a P300-based concealed information test. In CTP, each trial contains two stimuli: 1) A “Probe” (P--a relevant to the subject item (his/her birthday) or “Irrelevant” (I--any date, NOT relevant to the subject) and later, 2) A “Target” (T, an item with “assigned significance”) or “Non-Target” (NT, item without any specific meaning) The two stimuli are separated by about 1s. First, a date is presented (“Probe” or “Irrelevant”), then after about 1s, a string of numbers(11111) is presented ,T) or one of 4 NTs. Subject responds to first stimulus with an “I saw it” response button, whether P or I. Later, S makes T or NT button press. “I saw it” response box “Target/Nontarget” response box

3. Preparation of the stimuli (image/acoustic files). Task Construction and Stimuli Presentation: 3. Preparation of the stimuli 3. Preparation of the stimuli (image/acoustic files). Visual stimuli (Images) can be prepared in “Photoshop” or “Paint” and saved with an extension “jpeg” or “bmp.” For our experiments, where we use words as stimuli, we developed a special Photoshop template which allows us to change words promptly and keep all other image characteristic unchanged. Acoustic stimuli can be either beeps or words. For our acoustic experiments with words we use AT&T Text-to-speech software which allows creation of audible speech from computer readable text (demo version can be download from http://www.research.att.com/~ttsweb/tts/demo.php). “Beep” stimuli can be prepared in PSYTASK. Details on preparation visual and acoustic stimuli for PSYTASK can be found in PSYTASK manual.

Task Construction and Stimuli Presentation: 4. Probe/Irrelevant ratio 4. Stimuli ratio (stimuli probability issue) In P300 investigations a stimuli presentation protocol should be created so it includes rare and frequent stimuli. A “Probe/Irrelevant” ratio remains a controversial issue. In our protocols we use “Probe/Irrelevant” ratio from 1:4 to 1:8 (most recent).

Task Construction and Stimuli Presentation: 5. Structure of a trial. 5. Structure of a trial (simple or complex). For our experiments in our lab we use both simple and complex trials; In “simple” trials, there is one stimulus presented in each trial; In “complex” trials we have two(or more) stimuli following each other; We have decided to switch completely to “simple” trials, just dividing a complex (two stimuli) trial into two parts. Thus, each of the two parts contains only one stimulus in it. This way we reduce the number of rejected trials (with eye-blink artifacts) and increase the number of averaged trials;

Task Construction and Stimuli Presentation: 6. Stimuli exposition time Stimuli exposition time depends on the purpose of the ERP investigation and technological advances. In our P300-based “Deception” and “Malingering” studies we use stimuli exposition time in range of 100-300 ms (for visual stimuli) and 600-1200 ms (for acoustic stimuli).

Task Construction and Stimuli Presentation: 7. Trial duration. Fig. 10

Task Construction and Stimuli Presentation: 8. Inter-stimuli interval. 8. Inter-stimulus interval (sometimes called stimulus onset asynchrony/SOA -time between stimuli onset). Inter-stimulus (ISI) interval is determined by advance in technology (equipment limitation) and human sensory/cognitive processing abilities (human factor). With contemporary hardware and software ISIs could be as short as fractions of a second (~100ms) if the stimuli are simple and 300+ms for more elaborated stimuli. At the same time, human factor requires ISI to be long enough to let an ERP to emerge, develop, and reach it’s peak. Thus, normally ISI would fall within 500-3000ms.

Task Construction and Stimuli Presentation: 9. Total number of trials. To calculate total number of trials (N): One needs to know how many different groups of stimuli participate in the protocol and their ratio. For example: there are three groups of stimuli (Probe, Irrelevants, and Target) with the ratio 1:5:1 respectively. There have to be NO LESS than 20 trials for averaging in each of the groups (Cohen, J., Polich, J. 1997. “On the number of trials needed for P300.” International Journal of Psychophysiology 25, 249-255). Thus, n=(1x20)+(5x20)+(1x20)=140 Because people tend to blink and produce all other kinds of artifacts, we will need to record about twice as much trials to assure the necessary artifact-free number of trials (after cleaning artifacts). Thus, we come up with the following number of trials: N= 140x2= 280

Task Construction and Stimuli Presentation: 10. Trials Randomization. It is important to randomize trials, so trials containing rare probes and targets would be distributed among trials containing frequent irrelevant stimuli. Psytask is equipped with a special “randomization” feature. One can also use Microsoft Office Excel to randomize trials. After “randomization” it is important to go through the list of trials to make sure that the trials are randomized well enough and there are no back-to-back trials.

WS 8: ERP Protocols in Clinical Assessment In Part 2 we will consider some examples of ERP protocols for different conditions and purposes. The following examples are suggested for the demonstration: ADHD-1: Event-Related Potentials in the Evaluation of ADHD (Methylphenidate- and Nero-therapy). 1995 ADHD-2: Event-Related Potentials in the Evaluation of ADHD (“If-then” planning strategy).2007 PDD/Autism : Event-related potentials of self-face recognition in children with pervasive developmental disorders. 2009 Autism/MCDD/ADHD/Dyslexia: ERP Differences among Subtypes of Pervasive Developmental Disorders. 1999 Alzheimer’s Disorder/Mild Cognitive impairment: Diagnostic Value of Event-Related potentials N200 and P300 in Early Diagnosis of Alzheimer’s Disease and mild Cognitive Impairment.2007 Traumatic Brain Injury: The Effects of Increasing Stimulus Complexity in Event-Related Potentials and Reaction Time Testing: Clinical Applications in Evaluating Patients with Traumatic Brain Injury. 2007