NMDA hypothesis

1. What drugs can mimic schizophrenia?

a. Amphetamine-induced pyschosis (positive symptoms)

b. Ketamine (NMDA antagonist) elicits both negative and positive symptoms

NMDA antagonists are SUFFICIENT

Evidence that NMDA-mediated transmission is compromised in Schizophrenia

1. NAAG elevation in some patients

2. Elevation of kynurenic acid

3. Genes associated with schizophrenia

4. Mismatch negativity is an NMDA-dependent evoked potential recorded from the scalp. This is reduced in amplitude in schizophrenia.

5. Agents that enhance NMDA receptors (glycine site) appear to be therapeutic

1: Arch Gen Psychiatry. 2005 May;62(5):495-504.Related Articles, Links  Early-stage visual processing and cortical amplification deficits in schizophrenia.

Butler PD, Zemon V, Schechter I, Saperstein AM, Hoptman MJ, Lim KO, Revheim N, Silipo G, Javitt DC.

Nathan Kline Institute for Psychiatric Research, Orangeburg, NY 10962, USA. butler@nki.rfmh.org

BACKGROUND: Patients with schizophrenia show deficits in early-stage visual processing, potentially reflecting dysfunction of the magnocellular visual pathway. The magnocellular system operates normally in a nonlinear amplification mode mediated by glutamatergic (N-methyl-D-aspartate) receptors. Investigating magnocellular dysfunction in schizophrenia therefore permits evaluation of underlying etiologic hypotheses. OBJECTIVES: To evaluate magnocellular dysfunction in schizophrenia, relative to known neurochemical and neuroanatomical substrates, and to examine relationships between electrophysiological and behavioral measures of visual pathway dysfunction and relationships with higher cognitive deficits. DESIGN, SETTING, AND PARTICIPANTS: Between-group study at an inpatient state psychiatric hospital and outpatient county psychiatric facilities. Thirty-three patients met DSM-IV criteria for schizophrenia or schizoaffective disorder, and 21 nonpsychiatric volunteers of similar ages composed the control group. MAIN OUTCOME MEASURES: (1) Magnocellular and parvocellular evoked potentials, analyzed using nonlinear (Michaelis-Menten) and linear contrast gain approaches; (2) behavioral contrast sensitivity measures; (3) white matter integrity; (4) visual and nonvisual neuropsychological measures, and (5) clinical symptom and community functioning measures. RESULTS: Patients generated evoked potentials that were significantly reduced in response to magnocellular-biased, but not parvocellular-biased, stimuli (P = .001). Michaelis-Menten analyses demonstrated reduced contrast gain of the magnocellular system (P = .001). Patients showed decreased contrast sensitivity to magnocellular-biased stimuli (P<.001). Evoked potential deficits were significantly related to decreased white matter integrity in the optic radiations (P<.03). Evoked potential deficits predicted impaired contrast sensitivity (P = .002), which was in turn related to deficits in complex visual processing (P< or =.04). Both evoked potential (P< or =.04) and contrast sensitivity (P = .01) measures significantly predicted community functioning. CONCLUSIONS: These findings confirm the existence of early-stage visual processing dysfunction in schizophrenia and provide the first evidence that such deficits are due to decreased nonlinear signal amplification, consistent with glutamatergic theories. Neuroimaging studies support the hypothesis of dysfunction within low-level visual pathways involving thalamocortical radiations. Deficits in early-stage visual processing significantly predict higher cognitive deficits.

Electroencephalogr Clin Neurophysiol. 1998 Mar;108(2):143-53.Related Articles, Links

Impaired mismatch negativity (MMN) generation in schizophrenia as a function of stimulus deviance, probability, and interstimulus/interdeviant interval.

Javitt DC, Grochowski S, Shelley AM, Ritter W.

Nathan Kline Institute for Psychiatric Research/New York University School of Medicine, Orangeburg 10962, USA. javitt@nki.rfmh.org

Schizophrenia is a severe mental disorder associated with disturbances in perception and cognition. Event-related potentials (ERP) provide a mechanism for evaluating potential mechanisms underlying neurophysiological dysfunction in schizophrenia. Mismatch negativity (MMN) is a short-duration auditory cognitive ERP component that indexes operation of the auditory sensory ('echoic') memory system. Prior studies have demonstrated impaired MMN generation in schizophrenia along with deficits in auditory sensory memory performance. MMN is elicited in an auditory oddball paradigm in which a sequence of repetitive standard tones is interrupted infrequently by a physically deviant ('oddball') stimulus. The present study evaluates MMN generation as a function of deviant stimulus probability, interstimulus interval, interdeviant interval and the degree of pitch separation between the standard and deviant stimuli. The major findings of the present study are first, that MMN amplitude is decreased in schizophrenia across a broad range of stimulus conditions, and second, that the degree of deficit in schizophrenia is largest under conditions when MMN is normally largest. The pattern of deficit observed in schizophrenia differs from the pattern observed in other conditions associated with MMN dysfunction, including Alzheimer's disease, stroke, and alcohol intoxication.

Javitt DC, Steinschneider M, Schroeder CE, Arezzo JC.

If NMDA hypofunction is everywhere, are there special functions and brain regions where the consequences of NMDA hypofunction are particularly devastating?

1. Other forms of damage to the hippocampus can cause psychosis.

2. Hippocampal pathology (Benes)

3. Volume changes of the hippocampus

4. Hypoactivation of the hippocampus under basal conditions.

Normal

Schiz.

Comparison of sensory input to

Predicted input occurs in CA1

dentate CA3

CA1

Potential for positive feedback: mismatch generates more mismatch: stuck in “write only” mode.

A

PP SC60

70

80

90

100

C

PP SC

***

B

1 mV

5 msControlAP-5

PP

SC

Large NMDA component in perforant path (PP)

Work of Nonna Otmakhova in Lisman Lab

ClozapineControl

40

60

80

100

0 10 20 30 40 50 60

T I M E (min)dopamine min

Otmakhova and Lisman

Second action of dopamine: blocking the PP input to CA1

this effect of dopamine is blocked by clozapine

Hippocampal –VTA Loop

Hippocampus

VTA

Positive Feedback hypothesis

Connects dopamine and NMDA theories

Clozapine could break the positive feedback loop and thereby be therapeutic (supported by fact that clozapine makes hippocampus less active)

Anarchic Hand

Phantom Limbs

Parietal Neglect

Capgras Syndrome

Confabulation

Hallucinations

Delusions

Alien Control

Schizophrenia

1. Hallucinated voice speaking the patient’s thoughts out loud.

2. Hallucinated voices arguing about the patient.

3. Hallucinated voices describing the patient’s activity as it takes place.

4. The patient believes he is the passive recipient of sensations imposed from the outside.

5. The patient believes his thoughts/actions are controlled from the outside.

6. The patient believes his thoughts can be withdrawn from his mind.

Schneider’s First Rank Symptoms of Schizophrenia

Correct comparator function allows the conscious brain to determine whether a percept is generated by “other” or by one’s own unconscious

Unconscious generation

Generation by “other”

Lisman, 2005