PERCEPTION: Gain Control & Integration. Mark A. Geyer, Ph.D. Departments of Psychiatry & Neurosciences University of California, San Diego

Transcription

1 PERCEPTION: Gain Control & Integration Mark A. Geyer, Ph.D. Departments of Psychiatry & Neurosciences University of California, San Diego

2 Perception Integration Integration: The processes linking the output of neurons that individually code local (typically, small) attributes of a scene - into global (typically, larger) complex structure, more suitable for the guidance of behavior. Tasks nominated for further development: Coherent Motion Detection Task Contour Integration Task Modified to optimize assessment of integrative processes

3 Integration Tasks Coherent Motion Detection Task Contour Integration Task Both human tasks only in visual modality Behavioral and imaging measures Analogous tasks in cats and monkeys. Some proposed for rodents (e.g. Visual Discrimination of direction of motion) Most use electrophysiological, not behavioral measures Minimal pharmacology literature Perhaps rodent touch-screen methods could be used?

4 Perception Gain Control Gain control: The processes whereby neurons adapt their response levels to take into account their immediate context, in order to make best use of a limited dynamic signaling-range. Tasks nominated for further development: Contrast-Contrast Effect (CCE) Task Contrast Sensitivity + Steady state visual evoked potentials to magnocellular vs. parvocellular biased stimuli. Already mature tasks: Mismatch Negativity (MMN) Prepulse Inhibition of Startle (PPI)

5 Gain Control Tasks Contrast-Contrast Effect (CCE) Task Contrast Sensitivity + Steady state ERPs Both human tasks only in visual modality Behavioral and imaging measures Analogous tasks in cats and monkeys. Some proposed for rodents (e.g. Visual Discrimination of direction of motion and Auditory Frequency Discrimination ) Minimal pharmacology literatures Perhaps rodent touch-screen methods could be used?

6 Rodent Touch Screen Tasks Courtesy of Tim Bussey, Cambridge

7 Visual Discrimination Learning Courtesy of Tim Bussey, Cambridge

8 McCarthy, Owens, Bansal, McTighe, Bussey and Saksida (2011) Pharmacology, Biochemistry & Behavior Donepezil Facilitates Visual Discrimination 90 % Correct Baseline Don 0.1 Don 0.3 Don 1.0 Veh 60 Treatment

9 Gain Control Tasks Mismatch Negativity (MMN) Human task in auditory modality Electrophysiological and imaging measures, not behavioral Analogous electrophysiological task in mice, cats, and monkeys Limited pharmacology literature NMDA antagonists reduce MMN in humans, monkeys, and mice Well developed task: True for assessing deficits in schizophrenia Limited work in other disorders or rodent applications Not true in terms of use for testing improvements in gain control.

10 Gain Control Tasks Prepulse Inhibition of Startle (PPI) Human task in auditory, tactile, or cross-modal modalities Behavioral, electrophysiological, and imaging measures Homologous behavioral task in many species Enormous pharmacology literature in rodents; modest literature in humans Well developed task: True for assessing antipsychotics. Not true in terms of PPI-fMRI as a potential imaging biomarker Not true in terms of use for testing improvements in gain control.

11 Prepulse Inhibition & Latency Facilitation db 115 Pulse - Alone Trial Pulse Startle Reflex Amplitude 70 White Noise Onset Latency Peak Latency Time (ms) db /86 70 Prepulse Trial Prepulse White Noise Pulse Startle Reflex Amplitude 30/ 60/ 120/ 240 Time (ms) Prepulse Inhibition of amplitude is disrupted in Schizophrenia Latency Facilitation is normal in Schizophrenia

12 ross-species Homology: Startle/PPI

13 The Deficient Gating Construct NORMAL Sensory & Cognitive Information SCHIZOPHRENIA Sensory & Cognitive Information Pre- and Attentional Filters Deficient Filters Information Processing Information Overload Coherent Cognitive Schema Disorganized Cognition Braff & Geyer 1989

14 PPI is NOT Correlated with Other Gating Measures: In Mice, Rats, Healthy Humans, or Schizophrenia Patients Other operational measures of GATING: Startle habituation P50 auditory gating Latent Inhibition The more specific construct of Gain Control in perceptual processing fits well with the original pre-attentional filtering construct for PPI

15 Circuits Modulating PPI in Rats Frontal Cortex Hippocampus ACh GLUTAMATE GLUTAMATE Nuc. Acc. GLUTAMATE Amygdala DA Ventral GABA 5HT 5HT Pallidum Ventral Tegmentum GABA Raphe Nuclei Adapted from Swerdlow, Geyer & Braff, Psychopharmacology, 2001 Pedunculopontine Startle Reflex Circuit

16 fmri Z=-2 Z=0 Z=2 t value PPI Controls Increases in prepulse condition relative to startle-alone. Z=2 Z=4 Z=6 SZ Patients Less activity in patients than in controls. t value x=-2 y=-6 z=10 Thalamus x=-40 y=-4 z=10 Insular Cortex x=-46 y=-6 z=10 Inferior Frontal Gyrus Kumari, Antonova, Geyer, ffytche, Williams, Sharma, Int. J. Neuropsychopharmacology, 2007

17 Four Rat Models of Deficient PPI Psychostimulant Dopamine Agonists Apomorphine, Amphetamine Hallucinogenic Serotonin-2A Agonists DOI, Mescaline, LSD Psychotomimetic NMDA Antagonists PCP, Dizocilpine, Ketamine Developmental Disturbances Prenatal MAM, Isolation Rearing, Neonatal Lesions, Early postnatal PCP

18 Antipsychotic Effects in Four Rat Prepulse Inhibition Models Disrupting Manipulation Dopamine D2 Agonists Serotonin 2A Agonists NMDA Antagonists Developmental Perturbations Typical APDs Atypical APDs Others Yes Yes Some No Some No? No Some Some Yes Yes Yes? Geyer, Krebs, Braff, & Swerdlow, Psychopharmacology, 2001

19 Clozapine Increases Low PPI in C57BL/6J Mice 100 V E H H AL 1 H AL 3 H AL VEH CLOZ 0.3 CLOZ 1 CLOZ 3 80 CLO Z 30 %PPI Clozapine failed to increase PPI in the high PPI strain of mice (129Sv/Ev) Ouagazzal, Jenck, Moreau, Psychopharmacology, 2001

20 Clozapine Increases PPI in Low but not High PPI Subjects PLACEBO CLOZAPINE 80 PLACEBO CLOZAPINE %PPI ISI Low PPI Subgroup ISI High PPI Subgroup Vollenweider, et al, Biol Psychiatry, 2006

21 CONCLUSIONS Perceptual abnormalities may impact performance on cognitive tests and cognitive functions in patients. Cross-species tasks to assess Integration and Gain Control in visual and auditory domains are feasible. Developing visual modality tasks in rodents may help. Global constructs such as Gating may be less useful than specific constructs such as Gain Control. Tasks that are well developed for some purposes may require further development for assessing the constructs of Integration and Gain Control. Though beyond the scope of this meeting, combining a specific task with different disrupting manipulations will lead to different pharmacological profiles.

22