Table 1.

A multilevel view of disturbed associations in schizophrenia: Is there a common theme of failure of suppression/inhibition?

Clinical level:

Presence of thought disorder.

Bleuler: “associations which normal individuals will regard as incorrect, bizarre, and utterly unpredictable”.

Inference:

Loose associations are one of the fundamental disturbances of schizophrenia.

Behavioral experimental level:

Abnormal connectivity in connectionist network model.

High connectivity dominates, context less important.

Inference:

Failure of suppression of dominant associations = ? failure of context utilization.

Functional neural systems level:

N400 studies of language and word pairs.

Reduced N400 amplitude for word pairs when second word is related to first (short inter-word intervals).

Increased N400 to congruent sentence endings.

Inferences:

Faulty search of lexicon, as indexed by N400.

More dominant associations prevail. Failure to use context. Failure to suppress dominant associations.

Anatomical systems level:

MRI studies:

Reduced MRI gray matter volume in language processing areas of the brain (including superior temporal gyrus/Wernicke’s area).

Volume reduction correlated with the degree of thought disorder.

Inference:

Abnormal anatomical substrate for language in schizophrenia.

Cellular and molecular level:

In vitro model: Exogenous NMDA receptor blockers (Psychotomimetics) –

Suppress recurrent inhibition more than feed-forward excitation.

Disturbance in a ‘realistic’ neuronal model leads to failure to suppress previously learned Hebbian associative patterns.

Post-mortem data: Endogenous NMDA receptor blockers (NAAG) and/or other abnormalities affecting inhibitory neurons may be present in schizophrenia.

Inferences:

Failure of inhibition at the cellular level.

Possible excitotoxic effects of resultant abnormal excitation, and progression of neural tissue damage. Developmental anomalies secondary to NMDA abnormalities.