The proposed research will pilot a validity test for a technique that promises to enhance the ability to diagnose subtypes of disorders of attention and arousal. This enhanced ability to diagnosis correctly will support the choice of more appropriate treatments for these conditions. The current assessment of attention disorders (e.g., ADHD) is accomplished through multiple methods, including norm-based behavior rating scales (completed by parents and teachers for children and self-reports for adults), a structured interview, and the assessment of intellectual and academic/occupational functioning. Computerized and standardized Continuous
Performance Tests (CPT's) are widely used as a means of quantifying a person's ability to sustain attention across time (vigilance) and to inhibit impulsive/unwanted behavior (executive control). Used alone, CPT's are known to miss from 15-52% of the cases that would otherwise be diagnosed as ADHD using the former measures. The current assessment protocol should account for some percentage of those true cases of attention disorder that are missed currently by the CPT.
It is clear to science that the set of disorders falling under the diagnostic category of ADHD are primarily physiological in nature. It is a paradox, therefore, that the most common diagnostic approaches used currently fail to use physiological measures in the diagnosis of this category. The proposed research will use the currently accepted diagnostic procedures, while undertaking the piloting of an additional assessment that adds approximately 20 minutes to the process. This research will monitor a physiological response that reflects the activity of the neurochemistry underlying attention and arousal states (Ohlund, L.S., et.al., 1992), the Skin Conductance Response (SCR). This SCR measurement (of level of perspiration) will be collected simultaneously with the quantified behavioral measures of the CPT.
This research will serve as a preliminary testing of the validity of this technique to support the accurate and refined diagnosis of attention disorders (ADHD subtypes). In addition, specific hypotheses will be tested regarding changes in SCR activity during specific conditions of the behavioral CPT measure. It is predicted that the combined SCR and CPT assessment will distinguish at least five separate ADHD subtypes with differing underlying neurochemistry:
1) inattentive with hyperactivity characterized by low dopamine and high norepinephrine activity
The medication strategy (if indicated by the individual case) would differ for each of the above subtypes (Horacek, 1998).
The possibility of improving the approaches used currently to diagnose and treat disorders of attention and arousal makes this research of considerable significance to our society via the improved well-being of those affected by these disruptive symptoms.
2) inattentive alone characterized by low dopamine activity
3) hyperactivity alone characterized by high norepinephrine activity
4) hypoactive inattentive characterized by low dopamine and low norepinephrine activity
5) overfocused inattentive characterized low dopamine and high norepinephrine activity with possible altered serotonin activity.
Several pencil and paper diagnostic measures and a clinical interview are essential to conducting this research properly. These instruments (as described below in Dependent Variables: Section A) will be given to the subjects during their first testing session. It is estimated that this testing session will last approximately 2-3 hours. The Structured Clinical Interview DSM-IV-TR (SCID) will be used to determine the presence of any DSM-IV psychiatric diagnostic categories. The Edinburgh Handedness Inventory will be used to measure extent of lateralization of motor function. The Peabody Picture Vocabulary Test and Raven Progressive Matrices are respected measures of verbal and nonverbal cognitive ability and will serve as important neuropsychological adjuncts to the primary dependent variables as well as recognized estimators of intelligence. The CPT behavioral data is modulated by intelligence, making these measure necessary pieces of the research. Anxiety and depression are also modulators of the CPT behavioral data and clinical expressions of the neurochemical imbalances to be studied. The Spielberger State-Trait Anxiety Test and the Beck Depression Inventory are respected measures of these clinical states. The Wender-Utah Rating Scale and Conner's Adult ADHD Rating Scales are standard measures used for diagnosis and are necessary for this study. The Tridimensional Personality Questionnaire and the Dopamine-Serotonin-Noradrenaline Questionnaire (DSNQ) will be used to categorize the ADHD subjects along personality dimensions.
A second testing session will be scheduled for the experimental diagnostic testing. This session should last from 1 to 2 hours: including preparation, administration of the behavioral and psychophysiological measures, and debriefing of the subjects. The experimental testing will consist of the simultaneous collection of reaction time behavioral in response to the: A- Conner's Continuous Performance Test (CPT-II) and B - the psychophysiological measure of Skin Conductance Response.
A - Computerized Behavioral Testing (Conner's Continuous Performance Test-II):
The Conner's Continuous Performance Test (CPT-II) is one of several now in wide use for
the purpose of assessing a person's ability to sustain attention over time (Conner, 2000; Halperin, et. al, 1991)). This test requires the subject to monitor a computer controlled sequence of visually presented letters over a period of approximately 20 minutes. The subject is asked to respond with a key stroke as quickly as possible to the appearance of any letter on the screen, but to refrain from responding when the less frequent letter "X" appears. A long list of dependent variables, including the response times and standard error of response times in various conditions along with the frequency of error types, is generated by this standardized and objective test. For example, omission errors, or the failure to respond to a target letter (non-"X" stimuli), reflect inattention, whereas commission errors (responding to the non-target "X" stimuli) reflect impulsive tendencies (Dougherty, D. M. et. al., 2000). The results of the CPT-II testing will be analyzed according to the standardized clinical interpretation with a focus on the possibility on finding a neural substrate for the hypothesized ADHD subtypes (Riccio, et. al., 2002). The CPT-II dependent variables will also be analyzed using the amplitude change data from the psychophysiological measure, the skin conductance response, as described below.
B - Psychophysiological Testing (Skin Conductance Response):
The Skin Conductance Response (SCR), formerly known as the Galvanic Skin Response, is a reliable method of measuring activity of the autonomic division of the nervous system as a parameter of sweat gland function (Fowles, 1974; Venables & Christie, 1980). The SCR is triggered by an increase in sympathetic activity of the autonomic nervous system (norepinephrine stimulation of the sweat glands) following the onset of a startling event or stimulus (Gutrecht, 1994; Shibagaki, M., et. al., 1993). This physiological signal will be measured by the change in voltage across the skin and will be measured between two Ag/AgCl electrodes placed on palmar surface of the subjects' fingers. SCR amplitude (on average typically 0.52 microSiemen) has a typical response latency following an event of 1.2 - 1.8 seconds. This response may last for several seconds and may contain multiple (2-3) waveforms. A decrease in the amplitude of the SCR over the course of testing is associated with the weakening of arousal or alertness or of the weakening of the surprise effect of an event (c.f., Barry, R.J. et. al., 1993).
These data will be analyzed in a variety of ways. First, the peak amplitude of the first SCR wave generated following a stimulus will be determined. This peak response will be compared with the average SCR amplitude for the .5 second period prior to onset of the stimulus and used to calculate an amplitude difference score. The SCR difference scores for the different trial types generated by the CPT behavioral test will be used in parametric statistical tests to characterize differences between the different subjects groups. Secondly, the SCR waveforms will be analyzed via a multivariate statistical technique called principle component analysis (PCA). PCA reduces the dimensionality of a waveform dataset by determining the orthogonal vectors contained within a complex vector (such as the SCR). For this purpose, the data will be normalized and waveforms, not signal amplitude, will be the variable of interest. This separation of the SCR data will allow for analysis of the tonic and phasic components of the signal Adjustments will be made for age as indicated by the range of ages reflected in the dataset (Drory, V.E., et. al., 1993).
Data Analysis of the Multiple Behavioral and Psychophysiological Measures
This study will attempt to validate the use of the multiple variables mentioned above, generated by the multiple methods described above, for the purpose of diagnosing meaningful subtypes of ADHD. The classic statistical procedure for this type of experimental design (convergent and discriminant validation of measures) is the use of the multitrait-multimethod matrix (Campbell, D.T. & Fiske, D.W., 1959). Due to the pilot (and complex) nature of this study, the investigator will seek the consultation of a biostatitician for additional guidance. The investigator has always used the most rigorous of analysis procedures in her research and will continue this standard in the proposed research.
Subjects
Volunteer adults will be recruited via campus publications and relevant clinical offices in Saginaw, Bay City, and Midland. The clinicians in this region who diagnose ADHD on a regular basis are already in a database and the subject of a thorough survey of diagnostic and treatment practices. The investigator has prepared this survey study, which is scheduled to be mailed to the physicians in the database during March, 2003. A student who is a recipient of the university's Foundation Scholar Program, has chosen to support this project for her Community Service venture, and will be helping the principal investigator with these outreach activities.
No participants under the age of 18 will be studied during the initial stages of this research. Volunteer adults will be recruited via campus publications and relevant clinical offices in Saginaw, Bay City, and Midland. The clinicians in this region who diagnose ADHD on a regular basis are already in a database and the subject of a thorough survey of diagnostic and treatment practices. The investigator has prepared this survey study, which is scheduled to be mailed to the physicians in the database during March, 2003.
Demographic and individual characteristics known to moderate the study's dependent variables (SCR/GSR and CPT) will be collected and analyzed according to acceptable psychological scientific practice. Each subject's intelligence quotient will be estimated using the Peabody Picture Vocabulary Test (Verbal IQ) and the Raven Progressive Matrices- Standard and Colored (Nonverbal IQ).
Subject Criteria
Inclusion Criteria for Normal Control group
Inclusion Criteria for ADHD group
Exclusion Criteria for Normal Control group
Exclusion Criteria for ADHD group Dependent Variables – Summarized in Figure 1
A - Pencil-paper Clinical Diagnostic and Personality Measures for Adults: The Wender-Utah Rating Scale(WURS) is a self-rating instrument for adults of childhood behaviors. This scale aids in the retrospective diagnosis of childhood ADHD (Ward, et al., 1993; Stein, et al., 1995). It will be used in the present study to exclude a person with childhood ADHD symptoms from the normal control group as well as to establish the ADHD diagnosis in the ADHD experimental subgroups. The Conner’s Adult ADHD Rating Scale(CAARS) will be used along with the Wender-Utah Rating Scale to help establish the diagnosis of ADHD for the self-referred and physician referred volunteer subjects to be tested in this study. The Speilberger State-Trait Anxiety Scale (STAI) is designed to differentiate between the temporary condition of "state anxiety" and the more general and long-standing quality of "trait anxiety" in adolescents in high school through adulthood. The State Anxiety scale evaluates feelings of apprehension, tension, nervousness, and worry, which increase in response to physical danger and psychological stress. Anxiety levels are known to affect both the CPT and SCR dependent variables and it is therefore, necessary to account for level of anxiety in the analysis of these results (Epstein, J.N., et al., 1997; Quermonne, M.A., et al., 1993). The Beck Depression Inventory-II (BDI-II) is the most widely-used, validated measure of depression. It is a simple self-report 21-item instrument that quantifies level of depressive symptoms. Depression is found in up to 28% of adults diagnosed with ADHD and is a variable that needs to be addressed in this research (Barkley, R.A., 1998). The Dopamine-Serotonin-Noradrenaline Questionnaire (DSNQ) is a behavioral self-report measure that reflects imbalanced neurochemistry. This measure was developed by my collaborator, Dr. H. Joseph Horacek (1998), and will be used as the TPQ described above to form behavioral subgroups within the ADHD diagnosed subjects. These DSNQ generated ADHD subgroups will also be used to predict different CPT-II and SCR profiles based on the different underlying neurochemical profiles as described previously. The Tridimensional Personality Questionnaire (TPQ) is a 100 item, self-administered paper and pencil true-false instrument that takes approximately 10 minutes to complete (Cloninger, et al., 1991). This questionnaire measures three higher-order personality dimensions that influence how a person responds to stimuli and that have been linked to the brain systems and neurochemistry of importance to this study. The analysis of the genome of these personality traits is currently underway (Cloninger, et al., 1996). The three personality dimensions measured by the TPQ include: 1) Novelty Seeking or behavioral activation as maintained by dopamine, 2) Harm Avoidance or behavioral inhibition as maintained by serotonin, and 3) Behavioral Maintenance or reward dependence as maintained by norepinephrine (Cloninger, 1987; Cloninger, et al., 1993; Heath, et al., 1994). This questionnaire will be used to form behavioral/personality subgroups within the ADHD diagnosed subjects. These TPQ distinguished ADHD subgroups will be used to test hypotheses that predict different CPT and SCR profiles based on the different underlying neurochemical profiles as described previously. B - Computerized Behavioral Testing (Conner’s Continuous Performance Test-II): The Conner’s Continuous Performance Test (CPT-II) is one of several in wide use for the purpose of assessing a person’s ability to sustain attention over time (Conner, 2000; Halperin, et al, 1991)). This test requires the subject to monitor a computer controlled sequence of visually presented letters over a period of approximately 20 minutes. The subject is asked to respond with a key stroke as quickly as possible to the more frequently appearing letter “A”, but to refrain from responding when the less frequent letter “X” appears. A long list of dependent variables including the response times and standard error of response times in various conditions, along with the frequency of error types, is generated by this standardized and objective test. For example, omission errors, or the failure to respond to the target “A” stimuli, reflect inattention whereas commission errors (responding to the nontarget “X” stimuli) reflect impulsive tendencies (Dougherty, D. M. et al., 2000). The results of the CPT-II testing will be analyzed according to the standardized clinical interpretation with a focus the possibility of finding a neural substrate for the hypothesized ADHD subtypes (Riccio, et al., 2002). The CPT-II dependent variables will also be analyzed using the amplitude change data from the psychophysiological measure, the skin conductance response, as described below. C - Psychophysiological Testing (Skin Conductance Response): The Skin Conductance Response (SCR), formerly known as the Galvanic Skin Response, is a reliable method of measuring activity of the autonomic division of the nervous system as a parameter of sweat gland function (Fowles, 1974; Venables & Christie, 1980). The SCR is triggered by an increase in sympathetic activity of the autonomic nervous system (norepinephrine stimulation of the sweat glands) following the onset of a startling event or stimulus (Gutrecht, 1994; Shibagaki, M., et al., 1993). This physiological signal will be measured by the change in voltage across the skin between two Ag/AgCl electrodes placed on the palmar surface of the subjects’ fingers. SCR amplitude (Tonic activity: 1-3 microsiemens; Phasic activity: .05-5 microsiemens) has a typical response latency following novel stimulus of 1.2 – 1.8 seconds. This response may last for several seconds and may contain multiple (2-3) waveforms. A decrease in the amplitude of the SCR over the course of testing is associated with the weakening of arousal or alertness or of the weakening of the surprise effect of an event (c.f., Barry, R.J. et al., 1993). These data will be analyzed in a variety of ways. First, the peak amplitude of the first SCR wave generated following a stimulus will be determined. This peak response will be compared with the average SCR amplitude for the .5 second period prior to onset of the stimulus and used to calculate an amplitude difference score. The SCR difference scores for the different trial types generated by the CPT behavioral test will be used in parametric statistical tests to characterize differences between the different subject groups. Secondly, the SCR waveforms will be analyzed via a multivariate statistical technique called principle component analysis (PCA). PCA reduces the dimensionality of a waveform dataset by determining the orthogonal vectors contained within a complex vector (such as the SCR). For this purpose, the data will be normalized and wave shapes, not signal amplitude, will be the variable of interest. This separation of the SCR data will allow for analysis of the tonic and phasic components of the signal. Adjustments will be made for age as indicated by the range of ages reflected in the dataset (Drory, V.E., et al., 1993). Data Analysis of the Multiple Behavioral and Psychophysiological Measures This study will attempt to validate the use of the multiple variables mentioned above, generated by the multiple methods described above, for the purpose of diagnosing meaningful subtypes of ADHD. The classic statistical procedure for this type of experimental design (convergent and discriminant validation of measures) is the use of the multitrait-multimethod matrix (Campbell, D.T. & Fiske, D.W., 1959). References Anastopoulos, A.D. & Shelton, T.L. (2001). Assessing attention-deficit/hyperactivity disorder. New York: Plenum Publishers. Barkley, R.A. (1998). Attention-deficit hyperactivity disorder. New York : The Guillford Press. Barry, R.J., Feldmann, S., Gordon, E., Cocker, K.I. & Rennie, C., (1993). Elicitation and habituation of the electrodermal orienting response in a short interstimulus interval paradigm. International Journal of Psychophysiology, 15(3), 247-253. Campbell, D. & Foske, D.W. (1959). Convergent and discriminant validation by the multitrait-multimethod matrix. Psychological Bulletin, 56(2), 81-105. Cloninger, C.R. (1987). A systematic method for clinical description and classification of personality variants. Archives of General Psychiatry, 44, 573-588. Cloninger, C.R., Frzybeck, T.B. & Svrakic, D.M. (1991). The tridimensional personality questionnaire: U.S. normative data. Psychological Reports, 9, 1047-1057. Cloninger, C.R., Svrakic, D.M. & Przybeck, T.P. (1993). A psychobiological model of temperament and character. Archives of General Psychiatry, 50, 975-990. Clonninger, C.R., Adolfsson, R. & Svrakic, D.M. (1996). Mapping genes for human Personality. Nature – Genetics, 12, 3-4. Conner, C.K. & MHS Staff (2000). Conner’s continuous performance test II. Toronto : Multi-Health Systems. Dougherty, D.M., Bjork, J.M. & Marsh, D.M. (2000). A comparison between adults and conduct disorder and normal controls on a continuous performance test: Differences in impulse response characteristics. The Psychological Record, 50(2), 203-219. Drory, V.E., & Korczyn, A.D. (1993). Sympathetic skin response: age effect. Neurology, 43(9), 1818-1820. Epstein, J.N., Goldberg, C.K., Conners, C.K. & March, J.S. (1997). The effects of anxiety on continuous performance test functioning in an ADHD clinic sample. Journal of Attention Disorders, 2(1), 45-52. Fowles , D.C. (1974). Mechanisms of electrodermal activity. In: R.F. Thompson & M.M. Patterson (Eds.), Methods in Psychological Psychology. Bioelectric Recording Techniques - Vol. 1, 231-271, New York : Academic Press. Gutrecht, J.A. (1994). Sympathetic skin response. Journal of Clinical Neurophysiology, 11(5), 519-524. Halperin, J.M., Sharma, V., Greenblatt, E. & Schwartz, S.T. (1991). Assessment of the continuous performance test reliability and validity in a nonreferred sample. Psychological Assessment: A Journal of Consulting and Clinical Psychology, 3(4), 03-08. Heath, A.C., Cloninger, C.R. & Martin, N.G. (1994). Testing a model for the genetic structure of personality: A comparison of the personality systems of Cloninger and Eysenck. Journal of Personality and Social Psychology, 66(4), 72-775/ Horacek, H.J. (1998). Brainstorms: Understanding and Treating the Emotional Storms of ADHD from Childhood through Adulthood . New Jersey : Jason Aronson, Inc. Ohlund, L.S., Lindstrom, L.H. & Ohman, A. (1992). Electrodermal orienting response and central nervous system dopamine and serotonin activity in schizophrenia. Journal of Nervous and Mental Disease, 180(5), 304-313. Quermonne, M.A., Nammathao, B., Louchahi-Raoul, J. & Marcy, R. (1993). Skin conductance reaction (SCR)-habituation test and elementary model of anxiety as a tool to assess anxiogenic activities of some drugs. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 17(2), 311-318. Ricco , C.A. , Reynolds, C.R., Lowe, P. & Moore, J.J. (2002). The continuous performance test: A window on the neural substrates for attention?. Archives of Clinical Neuropsychology, 17, 235-272. Shibagaki, M., Yamanaka, T. & Furuya, T. (1993). Attention state in electrodermal activity during auditory stimulation of children with attention-deficit hyperactivity disorder. Perceptual and Motor Skills, 77(1), 331-338. Stein, M.A., Sandoval, R., Roizen, M.D., Reincke, M.A., Blondis, T.A. & Klein, Z. (1995). Psychometric characteristics of Wender Utah Rating Scale (WURS): Reliability and factor structure for men and women. Psychopharmacological Bulletin, 31(2), 425-433. Ward, M.F., Wender, P.H. & Reinherr, F.W. (1993). The Wender Utah Rating Scale: An aid in the retrospective diagnosis of childhood attention deficit hyperactivity disorder. American Journal of Psychiatry, 150(6), 885-890. Venables, P.H. & Christie, M.J. (1980). Electrodermal activity. In I. Martin & P.H. Venables (Eds.), Techniques in Psychophysiology, 2-7, New York : John Wiley.
o Male of Female volunteers aged 18-40 years old.
o Judged to be in good physical and psychiatric health on the basis of medical history.
o The Mini-Mental State Examination will be administered as a cognitive screen for healthy subjects, using a cut-off score of 27 (of total 30) for inclusion on the protocol.
o Able to understand procedures and agree to participate in the study by giving written informed consent.
o Free of childhood ADHD symptoms as indicated by the Wender Utah Rating Scale and the Conner's Adult ADHD Rating Scale.
o Criteria as above, except for the absence of childhood ADHD symptoms, plus a physician
diagnosis of ADHD.
o Confirmation of ADHD diagnosis using the Conner's Adult ADHD Rating Scale.
o Clinically significant organ disease, e.g., cardiovascular.
o Clinically significant abnormalities on basis of medical history.
o History of any disease, which in the investigator's opinion may confound the results of the study, including, but not limited to, history of organic mental disorder, seizure, or mental retardation.
o Lifetime history of substance dependence, or substance abuse within the past year.
o Psychotrophic medication within 2 weeks of testing.
o Criteria as listed above for Normal Control group
o Stimulant medication for treatment of ADHD within the window of time during which the particular medication is known to be effective.