Timing & Schizophrenia. Deana Davalos Colorado State University

Transcription

1 Timing & Schizophrenia Deana Davalos Colorado State University

2 What is Temporal Processing? (Thank you to all for background) In everyday terms Can I cross the street without being hit by a car? Do I have time to run by the post office before my meeting? Other types of activity affected by timing Athletic ability Musical ability Dancing Singing

3 Why is Temporal Processing Important? Planning and task sequencing (Mangels & Ivry, 2001) Language, prosody, communication (Breitenstein, et al., 2001; Montgomery, 2005) Understanding warning signals that predict future events (Tracy & Monaco, 1998) Associated with a number of diagnoses (e.g., Parkinson s Disease, ADHD, Alzheimer s Disease & Schizophrenia)

4 Why study Temporal Processing in Schizophrenia? (Thank you to Anne & Melissa) Anecdotal Observation Behavioral Measures Neurophysiological Indices Functional imaging (fmri) Implications & the importance of shiny things and good collaborators

5 Starting from the beginning. Auditory & Visual Temporal Deficits in Schizophrenia 10 Patients with SZ; 10 Controls Computer-based tasks of visual temporal perception and auditory temporal perception Davalos, Kisley, & Ross (2002)

6 Auditory Task Subjects compared interval durations in successive pairs of tones and were asked to decide whether the second interval was shorter or longer than standard interval. Each tone was 50 ms in duration Standard interval was 400 ms Pairs were separated by 1000 ms Half the trials were shorter (250, 280, 310, 340, 370 ms) Half the trials were longer (430, 460, 490, 520, 550 ms)

7 Number of Errors Auditory Temporal Perception Controls Patients Interval Duration in Milliseconds

8 Visual Task Subjects compared intervals in successive pairs of dots and were asked to decide whether the second interval was shorter or longer than standard interval. Each dot was presented for 50 ms in duration Standard interval was 400 ms Pairs were separated by 1000 ms Half the trials were shorter (300, 320, 340, 360, 380 ms) Half the trials were longer (420, 440, 460, 480, 500 ms)

9 Number of Errors Visual Temporal Perception 6 5 Control Patient Interval Durations in Milliseconds

10 Summary SZ exhibited deficits in differentiating interval durations compared to their control peers on both auditory (p <.01) and visual perception tasks (p <.01) The level of impairment appears consistent across the majority of deviants

11 Conclusions/Questions Deficits noted on the two tasks may represent a general temporal deficit in the SZ group. OR the ISI may also be a particularly problematic interval duration for SZ group.

12 Effect of Interstimulus Interval Duration Replicate the original findings with a larger sample and an increased number of trials Examine whether different interstimulus interval durations pose different levels of difficulty for the patients with SZ 16 patients with SZ and 15 controls The ISI separating the standard and experimental intervals varied in the range of 500, 1000, or 3000 ms. SZ group exhibit deficits for ALL ISIs (p <.001). (Davalos, Kisley, & Ross, 2003)

13 Effect of ISI Duration

14 Conclusion/Questions Seems to suggest a general temporal processing deficit in schizophrenia, but may be associated with poor attention to the task

15 Pre-Attentive Mechanisms of Temporal Processing Given that cognitive processes are implemented by the brain, it seems reasonable to assume that measures of neural activity can provide insight into cognitive processes. (Rugg and Coles, 1995) MMN is a negative component resulting from the difference in eventrelated potential (ERP) waveforms elicited by a standard and a deviant stimulus. It is usually studied in the absence of attentional requirements (Oades, et al., 1995)

16 Pre-Attentive Mechanisms of Temporal Processing 20 Controls 20 Patients with Schizophrenia Mismatch Negativity (MMN) Paradigm (Davalos, Kisley, Polk, & Ross, 2003)

17 Mismatch Negativity Negative difference wave that typically occurs between 100 and 250 ms after the deviant stimuli MMN is the deviantminus-standard difference wave

18 Mismatch Negativity FZ, CZ, PZ, Left & Right Mastoids Total of 4000 tones 50 ms in duration Interval of 400 ms Deviant interval of 340 ms occurring on average every 20th interval

19 Mismatch Negativity Subjects wear headphones and are played a train of tones Closed-Captioned movie and are recorded for approximately 28 minutes

20 ERP

21 Difference

22 SZ Average Difference

23 Control & Schizophrenia MMN Davalos, Kisley, Polk & Ross, 2003

24 Summary To this point. Results from computer-based studies of temporal processing suggest that patients with SZ exhibit temporal perception deficits Using a similar electrophysiological paradigm, patients continue to exhibit deficits compared to controls But

25 Conclusion/Questions Maybe the range in terms of difficulty levels is too small Maybe the task is too hard

26 Behavioral and MMN Indices of Temporal Processing in Schizophrenia PARTICIPANTS 30 controls 15 individuals meeting DSM-IV criteria for SZ PROCEDURE Behavioral Task: 200 trials 100 Easy Deviants 50% different 100 Difficult Deviants 15% different MMN: Two conditions (easy & hard) recordings counterbalanced 4000 trials per recording, 200 deviants in each procedure (Davalos, Kisley & Freedman, 2005)

27 Results MMN Results FZ Difficult Condition FZ Easy Condition Behavioral Results SZ subjects were impaired on BOTH conditions (p <.001)

28 Summary/Questions Results suggest that SZ patients have select neurophysiological TP deficits rather than generalized deficits Graded tasks may provide more information about cognitive and physiological processes in schizophrenia Behavioral tasks may involve additional cognitive processes that could potentially affect cognitive variable of interest

29 It s there behaviorally & physiologically (but different), what is going on in the brain? What brain structures are involved in time processing? Does activity change as a function of difficulty? Are there actually different patterns of activation associated with different levels of difficulty?

30 Imaging Time Processing 20 Controls Only Study 3T GE MR system equipped with high performance gradient coils Block design, where periods of an experimental task were interspersed with a baseline task Difficult trials and easy trials (Tregellas, Davalos & Rojas, 2006)

31 Easy Condition Activation Cerebellar Vermis - lesion studies (motor timing & TP) ; Medial cerebellar vermis specifically associated with tone duration estimation. Superior Temporal Gyrus (STG) - Attending to auditory processing P < 0.05

32 Difficult Condition Activation

33 Difficult Easy Activation Supplementary motor area (SMA); past timing studies, thought to be involved in performing complex tasks and early learning stages Insula/opercular cortex: attention to time; duration perception; auditory and visual rhythm perception; estimation (temporal sequencing) Putamen: encoding time intervals, formulating representations of time Dorsolateral PFC: working memory, cognitive control, selection of task-relevant information; temporal processing? P < 0.01

34 Time Processing in Schizophrenia Does the same pattern exist in schizophrenia? 18 individuals with SZ & 16 Controls 3T GE MR system equipped with high performance gradient coils Same Design Davalos, Tregellas & Rojas, 2010

35 By Condition Activation EASY Reduced activation in the schizophrenia group relative to controls DIFFICULT

36 By Condition Activation EASY Reduced activation in the schizophrenia group relative to controls DIFFICULT

37 So? Different areas of the brain are likely recruited for different types of TP tasks depending on difficulty May explain why different studies find different results May also explain why different TP tasks are related to different cognitive/behavioral variables ( PFC heavy tasks)

38 Conclusions/Questions We have a fairly nice story about temporal processing in adults with SZ Can we do anything about improving TP? Developmentally intervene? Psychopharmacologically intervene? Cognitively intervene?

39 Developmental Aspect SZ is believed to be a genetically transmitted disease. Research suggests that some cognitive deficits may be core deficits that present early in the course before more widespread deficits in adults with SZ (Davalos, Compagnon, Heinlein, & Ross, 2004) Could temporal processing be one?

40 Time Processing in Childhood-Onset Schizophrenia Participants 10 COS children/10 control children Age range: (8-14 yrs)/average age: (11yrs 4 mos) TP was measured as part of a larger neuropsychological battery Used the same auditory temporal processing task used in the adult studies (Davalos, Lavinder, & Ross, in progress)

41 Number of Errors Adult Schizophrenia vs. Childhood- Onset Schizophrenia AOS Controls Patients COS Control Patient

42 Summary Present in COS and AOS Deficits on select executive functioning measures (e.g., WCST), memory measures (CVLT-select scales), visuospatial tasks (block design) not present in COS, but are cited in AOS literature Timing may represent cognitive deficit that is present early in the course of SZ and less likely to result from chronic effects of disease

43 Conclusions/Questions Further research on what this timing problem means in childhood. can it be addressed? Is it present even earlier? Colleagues at UCDHSC

44 Back to.conclusions/questions We have a fairly nice story about temporal processing in adults with SZ Can we do anything about improving TP? Developmentally intervene? Psychopharmacologically intervene? Cognitively intervene?

45 Is there something we can administer to help those who have time processing deficits? Smoke a cigarette? Nicotine has been shown to improve cognition Past research suggests that the neuronal nicotinic acetylcholine receptor (nachr) system is integral to regulation of attentional processes and is dysregulated in schizophrenia. Question is whether it would also improve pre-attentive measure of timing in schizophrenia

46 (Martin, Davalos, & Kisley, 2009)

47 (Martin, Davalos, & Kisley, 2009)

48 (Guese, Davalos, & Kisley, Martin, submitted)

49 Conclusion/Questions Appears to help with preattentive, but need data on TP behavioral measures How long are the benefits Do the benefits in timing relate to any other cognitive gains?

50 Time perception (% accuracy) To what does timing relate? Relation of TP to Attention and Working Memory Sustained Attention (CPT) & Working Memory (LN) and Three TP conditions (400, 2000, 6000 msec) All TP conditions highly correlated No TP conditions related to attention Only 6000 ms & WM showed trend towards significance (p <.10) Letter-number span (number correct items) 20.00

51 To what does timing relate Part II Relation of time perception to other cognitive tasks Four attention/working memory tasks (Letter Number Span, Digit Span, Spatial Span, Temporal Order) and a time perception task. All working memory tasks highly correlated, none correlated with TP 6000 ms ISI 400 ms 310 ms 340 ms 355 ms 370 ms 430 ms 445 ms 460 ms 490 ms

52 How about timing and it s relationship to personality and other skills? Relation of time perception to perceptions of timing abilities, athletic participation, & music participation Associated with endorsement as athlete (p<.06) Musician endorsement not as strong And those who often rely on clocks and timer to remember events are the best on the timing test???

53 Next Step Continue research to understand the relationship of time processing to other variables (e.g. cognitive, personality, functional measures) Explore ways to improve time processing Stay on direct and linear path of research

54 My Future Timing Interests..Simplified Pathological Aging Normal Aging Aging Development Maternal Depression Infancy Childhood Pathological Development Normal Development Nicotine Pharmacology Timing Problems Clinical SZ COS Executive Functioning Working Memory Cognition Neuroscience ERP Temporal Order MEG fmri

55 Thank you! Acknowledgements CSU colleagues & lab members UDCHSC colleagues (Michael Kisley, Randal Ross, Jason Tregellas, Laura Martin, Don Rojas & Robert Freedman) Questions/Comments