Cognitive dysfunction in schizophrenia: unifying basic research and clinical aspects

Abstract

Seeking to unite psychological and biological approaches, this paper links cognitive and cellular hypotheses and data about thought and language abnormalities in schizophrenia. The common thread, it is proposed, is a dysregulated suppression of associations (at the behavioral and functional neural systems level), paralleled by abnormalities of inhibition at the cellular and molecular level, and by an abnormal anatomical substrate (reduced MRI gray matter volume) in areas subserving language. At the level of behavioral experiments and connectionist modeling, data suggest an abnormal semantic network connectivity (strength of associations) in schizophrenia, but not an abnormality of network size (number of associates). This connectivity abnormality is likely to be a preferential processing of the dominant (strongest) association, with the neglect of preceding contextual information. At the level of functional neural systems, the N400 event-related potential amplitude is used to index the extent of "search" for a semantic match to a word. In a short stimulus-onset-asynchrony condition, both schizophrenic and schizotypal personality disorder subjects showed, compared with controls, a reduced N400 amplitude to the target words that were related to cues, e.g. cat-dog, a result compatible with behavioral data. Other N400 data strongly and directly suggest that schizophrenics do not efficiently utilize context.

Fig. 1

N400 in schizophrenia and schizotypal personality disorder. Left panel gives examples of congruent and incongruent sentence endings. The right panel shows grand average waveforms from normal control subjects, schizophrenic subjects, and schizotypal personality disorder subjects to congruent sentence endings. Note that the schizophrenic and schizotypal personality disorder subjects both show an N400 (carat) to congruent sentence endings, a response found in controls to incongruent endings only. (“N400” reflects the latency (400 ms) of visually presented stimuli; auditory presentation, done in this experiment, produces a ≈ 100 ms shorter latency “N400”.)

Fig. 2

Left Panel. Left lateral view of a three dimensional reconstruction of the cortex, with pink indicating the anterior portion and red the posterior portion of the superior temporal gyrus (STG). Right Panel. SPGR coronal image (1.5 mm thick, 0.9375 × 0.9375 mm in plane voxels), showing the manually drawn outlines of regions of interest. L = left and R = right side for subject. The anterior-posterior location of this coronal slice is just posterior to the onset of the posterior portion of the STG in the left panel and is from the same subject. The regions of interest outlined are: the gray matter of the superior temporal gyrus (STG; subject left, red; subject right, green); more medially, the amygdala-hippocampal complex is shown (left, orange; right, blue) with the parahippocampal gyrus underneath (left, pink; right, purple). Adapted from Hirayasu et al. (1998)

Fig. 3

Cellular model of failure of recurrent inhibition. + is excitatory (glutamatergic) and – is inhibitory (GABA-ergic) synapse. The two horizontal lines on the projection neuron’s synapse with the GABA-ergic neuron represent NMDA receptor blockade. Note that inhibitory interneuron also has cholinergic, serotonergic, and dopaminergic modulatory synapses. These are also possible sites of abnormal receptors and/or abnormal inputs. See text for further discussion

Fig. 4

Long-term potentiation (LTP) of recurrent inhibition as a mechanism for controlling aberrant spread of lateral excitation. It results in confusion of normally distinguishable patterns of neuronal activity elicited by different inputs. LTP can be thought of as a strengthening of influence of connections by a Hebbian-like learning rule. This is a network biophysical simulation showing activity during recall; activity during learning is not shown. Parts A and B. Action potential activity induced in a network of 240 pyramidal cells without any strengthening (LTP) of excitatory intrinsic synapses. Each enclosed panel contains 240 neurons plotted in a 15 × 16 matrix. The size of the black squares represents the number of action potentials generated by each pyramidal cell during a 500 ms period of recall, as illustrated in membrane potential traces of neurons 191 and 175 to the right of Pattern #2 (Part B). The black square for 191 represents the six action potentials generated by that neuron, which receives direct afferent input. The absence of a black square for 175 represents the absence of action potentials due to the absence of afferent input to this neuron. For each pattern, the left panel shows the response to the complete input version of the pattern (with 40 neurons active) and the right square shows the response to a degraded input version of the pattern (with 24 neurons activated by afferent input). Parts C and D. Action potential activity in the network after learning strengthens the excitatory connections between active neurons (Excitatory LTP). The network has been trained on both pattern 1 and pattern 2, but recall is only shown for the complete and degraded version of pattern #2. Activity is shown during a 500 ms recall period. Part C. Inhibitory LTP present. Part C shows activity with the strengthening of synapses between pyramidal cells and inhibitory interneurons by inhibitory LTP. With both excitatory LTP and inhibitory LTP, the network responds to the complete pattern with no excess spread of activity, and responds to the degraded input with activity spreading only into neurons which were a component of the original learned pattern. For example, on the right the membrane potential traces show neuron 191 responding to afferent input, while neuron 175 responds due to synaptic activity spreading from other neurons. Part D. Absence of inhibitory LTP. With excitatory LTP but without inhibitory LTP, the network responds to both the complete and degraded versions of pattern #2 with activity which spreads to components of the other stored pattern, pattern #1. This is due to the spread of activity from neurons which were components of both patterns. This additional spread can be prevented by stronger recurrent inhibition. On the right, membrane potential traces show the response of neuron 191 and the excess spread of activity into neuron 161. In this case, differentiation of the two patterns is prevented because input of either pattern recalls elements of both patterns. (Adapted from Grunze et al. 1996)