psychotic disorders of the brain: basic and clinical neuroscience better outcomes cameron s. carter...
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Psychotic Disorders of the Brain: Basic and Clinical Neuroscience
Better Outcomes
Cameron S. Carter MD
Department of Psychiatry and
Center for Neuroscience
Overview
• What we know about brain pathology in schizophrenia and bipolar disorder
• How we are using this knowledge to improve outcomes
3 types of symptoms
• Positive• Negative• Cognitive/disorganization
Is schizophrenia a brain disorder?
JOHNSTONE AND CROWLANCET 1976
Effects of hemodynamic activation on BOLD signal in the brain: a) paramagnetic properties of Hb and b) overly zealous regulation of perfusion of the brain
Higher Cognitive Functions In Schizophrenia
• Attention• Memory• Language Disturbances• Emotional processing• Manifestation of Impaired Cognitive
Control
Cognitive Control
..when habitual responding won’t do and you have to use a representation of a task or goal to guide behavior…
GREEN
Gross Functional Impairment in the BrainMacrocircuit Abnormalities
Yoon et al, American J. Psychiatry 2008
Neuronal Oscillations?
* Encoding and processing occurs when a population of neurons fires at the same time AND with the same frequency.
Asynchronous firing
Synchronous firing
• Sometimes populations of neurons will fire at different times from each other (asynchronously), and sometimes they fire together (synchronously).
Frontal Cortical Induced Gamma Band Activity
Disrupted cortical function in schizophrenia
• Selective reduction in gray matter thickness• Subtle alterations in cellular structure and
function, unbalancing excitation and inhibition• Disrupted local circuit function• Loss of prefrontal control of networks• Negative symptoms and cognitive impairment• What about positive symptoms?
McGlashan 1984-the Chestnut lodge study
Alterations in dopamine neurotransmission
• The classical dopamine hypothesis (too much dopamine in schizophrenia) rested on the observation that DA releasing drugs can cause psychosis, and the discovery that antipsychotics were dopamine antagonists.
Alterations in dopamine neurotransmission
• C11 Racolpride displacement reflects DA release
Increased subcortical DA related to psychosis
Alterations in dopamine neurotransmission
• Decreased prefrontal activity (DA based or otherwise) may lead to subcortical DA dysregulation and psychosis
DecreasedPFC function
VTA
IncreasedDA
+
Improving Outcomes
• New therapies for negative symptoms and cognitive impairments– Medication treatments– Brain training– Brain Stimulation
• Early Intervention
Medication Treatment for Cognitive and Negative Symptoms
• Not dopamine blockers, added on to antipsychotic treatment
• Most target cortical function, especially the prefrontal cortex
• Increase neuromodulators, dopamine, norepinephrine, cholinergic/nicotinic, gaba-ergic to improve local circuit function
• No unequivocal successes yet but progress
Cognitive Training
• Many approaches being developed• Not just for schizophrenia, also ADHD,
MCI
Vinogradov/Posit Science Study Protocol
AUDITORY MODULE50 hours
VISUAL MODULE30 hours
COGN.CONTROL MODULE20 hours
Assessment Assessment Assessment Assessment
Assessments: Clinical and NeuropsychBloods (BDNF, serum antichol, plasms neuroleptic levels)MEG, fMRI
Baseline Cognitive Performance
Auditory Training Subject Group (AT) N = 40Computer Games Control Group (CG) N = 30
Baseline Cognitive Performance
-3.00-2.50-2.00-1.50-1.00-0.500.00
GlobalCognition
Speed ofProcessing
VerbalWorking
Mem
VerbalLearning +
Mem
VisualWorking
Mem
VisualLearning +
Mem
ProblemSolving
Z-Sc
ore
CG (N=30) TCT (N=40)
Change in Cognitive Performance
post-training minus baseline age-adjusted z-scores50 hours of computerized neuroplasticity-based auditory training (AT)
vs. 50 hours of a computer games (CG) control condition.
Results of Repeated Measures ANOVA, controlling for age and baseline cognitive performance, showed significant differences between AT and CG subject groups on measures of Global Cognition, Verbal Learning and Memory, and Verbal Working Memory at trend level.
Baseline to Post-Training Z-score Change
-0.60-0.40-0.200.000.200.400.60
**GlobalCognition
Speed ofProcessing
*VerbalWorking
Mem
**VerbalLearningand Mem
VisualWorking
Mem
VisualLearningand Mem
ProblemSolving
Z-Sc
ore
Chan
ge
CG (N=30) TCT (N=40)
PRELIMINARY 6-MONTH DATA: DURABILITY(AT = 22, CG = 10)
Fisher, Holland, Subramaniam, Vinogradov, Schiz Bull, 2009
Brain Stimulation
• Transcranial Magnetic Stimulation• Direct Current Stimulation
http://earlypsychosis.ucdavis.edu
Early Intervention for Psychosis
• Duration of untreated psychosis a strong predictor of treatment response and long term outcome
• Typically about 18 months in the US• Early identification and intervention to
brain this down• Established psychosis• The “psychosis risk syndrome”
PACE, PRIME, OPUS and PIER12 month outcome
EDAPT Model• Family based approach• Rapid, crisis-oriented initiation of treatment• Expert evaluation of clinical and risk status!!!• Psychoeducational multifamily groups• Case management and Medical Management using key
Assertive Community Treatment methods– Integrated, multidisciplinary team; rapid response;
continuous case review– Targeted pharmacological intervention as needed!!!
• Supported employment and education• Collaboration with schools, colleges and employers• Substance abuse treatment, as indicated• Detailed outcomes measurement
The EDAPT Program/SacEDAPT
U.C. Davis InnovationOvercoming Schizophrenia and
Bipolar Disorder
Overcoming Schizophrenia and Bipolar Disorder 1 person at a time
Basic research into brain development and function CENTER FOR
NEUROSCIENCE
Early Intervention EDAPT/SacEDAP
T
Novel Treatments for Cognitive Deficits and Negative Symptoms
TCAN Group
Division of Clinical Neuroscience
UC Davis Friends of Psychiatry
REGISTER ONLINE AT http://cme.ucdavis.edu/conferences