Timing Impairments and Neural Dysfunction in Basal Ganglia Disorders

Transcription

1 Timing Impairments and Neural Dysfunction in Basal Ganglia Disorders Deborah L. Harrington University of California, San Diego Veterans Affairs San Diego Healthcare System Co-Investigators University of California, San Diego Veterans Affairs San Diego Healthcare System, California USA Gabriel N. Castillo, David D. Song, Christopher H. Fong, Jason D. Reed, and Roland R. Lee Cleveland Clinic, Cleveland, Ohio USA Stephen M. Rao, Katherine A. Koenig, Svetlana Primak, and Sally Durgerian University of Iowa, Iowa City, Iowa USA Jane S. Paulsen

2 Time expansion/compression Properties of stimuli intensity novelty magnitude sensory modality Behavioral context externally versus internally guided timing predictability Core cognitive functions attention memory executive functions (decision making)

3 Corticostriatal anatomical connectivity Clock Signal (tonic dopamine/glutamate) phasic dopamine Core Timer Striatal Beat Frequency Model (Matell & Meck, 2004) Striatum Receives cortical oscillatory activity, which evolves as function of event duration Detects state of oscillatory pattern & responds when pattern matches reinforced state Dopamine (DA) Tonic DA & glutamate alter cortical oscillation frequencies Phasic DA signals onset/offset of timed event & strengthens synapses in striatum activated by beat frequency pattern

4 Parkinson s Disease (PD) Neuropathology Dopamine cell loss in nigrostriatal and to lesser extent, mesocortical pathway Symptoms Motor (tremor, rigidity, slowness, postural instability, freezing) Cognitive (executive, processing speed, visuospatial) Other (speech, sensation, sleep, mood, smell) Clinical Heterogeneity of Symptoms motor (tremor vs non-tremor dominant) domains of cognitive symptoms response to medication day-to-day fluctuation in symptoms

5 Timing in Parkinson s disease (PD) Temporal processing deficits in PD [Pastor et al, 1992; Rammsayer 1997; Harrington et al, 1998, 2011; Malapani et al, 2002; Elsinger, et al, 2003; Perbal et al, 2005; Smith et al., 2007; Jones et al., 2008, 2011; Merchant et al, 2008; Koch et al, 2008] Timing dysfunction is clinically relevant Freezing of gait or finger movements improved by pacing cues [McIntosh et al, 1997; Vercruysse et al, 2012] Brain mechanisms not well understood Time reproduction (fmri and PET) [Cerasa et al, 2006; Yu et al., 2007; Jahanshahi et al, 2010] Functional significance of abnormal activity in classic motor systems unclear (e.g., striatum, cerebellum) Effect of dopamine on brain activation not understood [Jahanshahi et al, 2010]

6 percent signal change Neural control of time perception in PD Study Participants 19 neurologically intact adults 21 PD without cognitive impairment groups similar in age and education level UPDRS motor subscale OFF (29.6, SD=10.4) ON (22.8, SD=8) Cortical & striatal volume normal in PD BOLD fmri detects localized changes in cerebral blood volume, flow, & oxygenation correlates with neural activity excellent spatial resolution, sluggish temporal resolution Time Perception Task Time (seconds) Image Acquisition n

7 fmri task design and hypotheses Phase of Trial DECISION 12 to 24 s post-trial onset 6 sec ENCODING 0 to 12 s post-trial onset Phase Processes Neural Systems Dopamine Encoding timing WM maintenance striatum, SMA improve striatal activation Decision timing executive processes striatum, SMA, MFG improve striatal activation cortex?

8 Percent Longer Behavioral results Time discrimination worse in PD than controls [group X comparison interval, p<.005] Dopamine therapy did not improve time discrimination No group differences in reaction time 100 Auditory Visual Control Group PD OFF PD ON Comparison Interval (% difference from standard interval) Harrington et al, PLoS One, 6(2), 2011

9 Regional activation results (PD OFF & controls) Encoding motor circuit executive circuit limbic system & vermis Decision striatum memory retrieval network sensory (vermis) No group difference Group difference Harrington et al, PLoS One, 6(2), 2011

10 Regional activation and dopamine (encoding) PSC PSC PSC PSC PSC PSC PSC Executive Motor Circuit Dopamine restores limbic and sensory system activation Sec post-trial onset Sec Sec post-trial onset onset Harrington et al, PLoS One, 6(2), 2011

11 Regional activation and dopamine (decision) PSC PSC PSC PSC PSC Dopamine improves putamen and normalizes vermis activation Striatum and Vermis Memory System Sec post-trial onset Harrington et al, PLoS One, 6(2), 2011 Sec post-trial onset

12 Effective connectivity of striatum Regional activation is impoverished measure of brain functioning Does dopamine alter connectivity of striatum with cortex and cerebellum? Psychophysiological interaction (PPI) method Seed regions caudate and putamen PPI regressor deconvolved time series for seed X medication status (OFF, ON) Tests if correlation of a seed time-series with time series of other brain voxels differs OFF and ON medication [Friston et al., 1997] Harrington et al, PLoS One, 6(2), 2011

13 Connectivity modulated by dopamine in decision phase Connectivity typically stronger OFF than ON medication Left Putamen SFG insula SMA precuneus Left Caudate MFG precentral SP Right Putamen pre/postcentral Right Caudate MFG precentral IP pre/postcentral precentral pre/postcentral Harrington et al, PLoS One, 6(2), 2011

14 Conclusions PD disrupts functional activity in core-timing, executive, memory, and sensory-integration systems Encoding phase core timing system (striatum) motor circuit (SMA, precentral) executive circuit (MFG, IPL, cerebellum) limbic (insula, parahippocampus) sensory (vermis) Decision phase core timing system (striatum) memory retrieval hub (posterior cingulate, parahippocampus) sensory (vermis) Is corticostriatal connectivity altered in PD during timing? Timing emerges from interactions among brain regions, not isolated process within a specific region

15 Conclusions DA did not alter timing proficiency and effects on regional activation were limited insula, parahippocampus, & vermis (encoding) putamen & vermis (decision) DA altered striatal connectivity Encoding phase No effect on connectivity does not mean that that corticostriatal connectivity is absent Decision phase DA reduced connectivity strength of striatum with motor circuit, middle frontal-parietal cortices, and insula DA depletion produces excessive synchronicity in corticostriatal circuits (Costa et al., 2006; Gatev et al., 2006; Hammond et al., 2007) Stronger resting-state connectivity (fmri, MEG) in PD OFF than ON medication (Stoffers et al., 2008; Baudrexel et al., 2011; Kwak et al., 2010) Why does DA alter connectivity only in decision phase? Mesocortical dopamine (tonic) stabilizes cortical oscillatory activity; important for encoding/maintenance Nigrostriatal dopamine (phasic) improves updating/integrative functions of basal ganglia; important for decision making Cools, Neurosciences and Biobehavioral Reviews, 2006

16 Preclinical Huntington Disease (prehd) PREDICT-HD Study PI: Jane Paulsen, University of Iowa Longitudinal observational study, now in 10 th year 32 sites (US, Canada, Australia, UK, Spain, Germany) Potential clinical and biological markers of HD in non- diagnosed gene-positive individuals (preclinical HD) Gene-negative individuals with family history of HD (control subjects) Estimated time to diagnosis varies from 5 to 25 years

17 Huntington Disease genetics and symptoms Caused by polyglutamine (CAG) expansion in coding region of huntington gene on chromosome 4 Usually manifests in midlife, but wide variation in age of onset Inverse correlation between age of onset and CAG repeat length HD diagnosis made at appearance of unequivocal motor signs (dyskinesias, oculomotor and gait abnormalities, rigidity, bradykinesia, hyper-reflexia)

18 Pathological changes Mutant huntingtin protein expressed throughout brain, yet disease is regionally specific Medium spiny neurons of caudate most vulnerable, but also putamen Less marked neuronal loss in cortex and other subcortical regions Pathological changes decades before diagnosis (striatal and cortical atrophy, cortical thinning, white-matter changes) Preclinical HD: Estimated Years to Diagnosis > 15 years 9 to 15 years < 9 years Figure adapted from Nopoulos et al, Neurobiology of Disease, 40, 2010.

19 Preclinical HD and cognition Pathological changes produce subtle motor, psychiatric, and cognitive changes more than a decade before diagnosis Poorer attention, working memory, processing speed, learning, executive functions, sensory-perceptual processing, emotion perception Impaired motor timing (self-paced) and time perception [Rowe, et al., Neuropsychology, 24, 2010; Paulsen et al., AJNR, 25, 2004; unpublished internal analyses of PREDICT-HD data] Timing dysfunction is clinically relevant Cross-sectional studies: Motor timing variability one of most sensitive measures of proximity to diagnosis Longitudinal studies: Motor timing variability worsens as individuals approach diagnosis Brain mechanisms not understood

20 Neural bases of timing deficits in prehd estimated years to Dx Control (n=32) Age 50.5 (9.4) Low (n=21) Medium (n=21) High (n=17) > < (10.0) CAP score (33.1) 39.0 (9.7) (21.9) 49.8 (13.9) (63.7) Basal Ganglia Volume All prehd groups L caudate & GP atrophy High prehd group B putamen, r caudate, & r GP atrophy Time Perception Task Response: longer/shorter Comparison (960 to 1500 ms) 1 sec delay Standard (1200 ms) Sensorimotor Control Task Response: press key 2 nd Tone (1200 ms) 1 sec delay 1 st Tone (1200 ms) Warning Warning

21 fmri design and hypotheses froi Methods To adjust for low-level sensory and motor activation, control task subtracted from time perception task Regions showing greater activation in the time perception task than the control task identified for each group served as froi in the data analyses Main Hypotheses Timing impairments will be more marked in prehd closer to diagnosis Timing deficits will be notable in the executive circuit (caudate, middle frontal and posterior parietal cortex)

22 Behavioral results Percent longer responses lower in high group Point of subjective equality (PSE) higher in high group No group effects for difference limen (DL) or coefficient of variation (CV) PreHD close to diagnosis underestimated time * ** *p<.05; **p<.01

23 froi associated with time discrimination bilateral caudate and thalamus R middle frontal, bilateral inferior parietal SMA/preSMA, anterior cingulate bilateral insula left inferior frontal, precentral left cerebellum (culmen, pyramis)

24 Preliminary fmri results Hyperactivation: Executive Circuit * * * * * * * * * * No group differences in caudate activation

25 Preliminary fmri results Hyperactivation: Anterior Insula & SMA/preSMA * * * * * * *

26 Genetic burden and brain activation Disease burden (CAP score) correlates with activation r age p value Executive Circuit R middle frontal (BA 9, 46) L inferior parietal (40) R thalamus L thalamus Motor Circuit SMA/preSMA (6) Limbic System L anterior insula.31.02

27 Preliminary conclusions PreHD close to diagnosis underestimate time Compensatory activity typically more than a decade before diagnosis in thalamus, executive circuit (MFG, parietal), SMA/preSMA, and anterior insula Hyperactivation correlates with genetic burden Functional changes precede timing impairments in prehd further from diagnosis Unknown if functional changes in cortex precede structural changes Functional role of striatum unclear adjust for individual differences in striatal volume (fmri analyses) investigate striatal connectivity

28 Overall summary Time discrimination deficits in PD and prehd Time underestimated in prehd Timing variability increased in PD Abnormal cortical activity seen in some common systems SMA/preSMA, MFG, inferior parietal, insula [e.g., Harrington et al, 1998; Pouthas et al, 2005; Wittmann et al, 2010] typically hypoactivation in PD hyperactivation in prehd (compensation?) Other sources of neuronal dysfunction in PD functional changes in striatum memory hub (parahippocampus, posterior cingulate) [Olton et al, 1987; Melgire et al, 2005] working memory (lateral cerebellum) [e.g., Desmond et al, 1997; Desmond, 2001; Chen & Desmond, 2005]

29 Future directions Functional connectivity of brain networks Many different connectivity approaches Advance understanding of how timing emerges from functional integration in brain circuits More sensitive to changes in core timing systems in neurodegenerative disorders More sensitive to pharmacotherapy effects specific brain networks Brain mechanisms of time compression/expansion Properties of stimuli affect perceived duration [Harrington et al, 2012; Wittmann et al, 2010] Modality effects on time are altered with maturation and in schizophrenia [Droit-Volet et al, 2007; Penney et al, 2005; Carroll et al, 2008] Intersensory timing Experience of time emerges through synthesis of information between senses Animal models: striatum involved in multisensory integration [Nagy et al, Euro J Neurosci, 2006] Corticostriatal networks support intersensory timing [Harrington et al, Frontiers Integrative Neurosci, 2012]