Sensory processing dysfunction in the personal experience and neuronal machinery of schizophrenia

Abstract

Sensory processing deficits, first investigated by Kraepelin and Bleuler as possible pathophysiological mechanisms in schizophrenia, are now being recharacterized in the context of our current understanding of the molecular and neurobiological brain mechanisms involved. The National Institute of Mental Health Research Domain Criteria position these deficits as intermediaries between molecular and cellular mechanisms and clinical symptoms of schizophrenia, such as hallucinations. The prepulse inhibition of startle responses by a weaker preceding tone, the inhibitory gating of response to paired sensory stimuli characterized using the auditory P50 evoked response, and the detection of slight deviations in patterns of sensory stimulation eliciting the cortical mismatch negativity potential demonstrate deficits in early sensory processing mechanisms, whose molecular and neurobiological bases are increasingly well understood. Deficits in sensory processing underlie more complex cognitive dysfunction and are in turn affected by higher-level cognitive difficulties. These deficits are now being used to identify genes involved in familial transmission of schizophrenia and to monitor potentially therapeutic drug effects for both treatment and prevention. This research also provides a clinical reminder that patients' sensory perception of the surrounding world, even during treatment sessions, may differ considerably from others' perceptions. A person's ability to understand and interact effectively with the surrounding world ultimately depends on an underlying sensory experience of it.

Figure 1

Anatomy of brain sensory systems, A. Cortical areas responsible for perception and executive function have both experienced especially enhanced expansion in the evolution of human brain (from 5). B. Right side of the brain shows auditory responses from the inner ear, conveyed through brainstem relay nuclei, arriving at the auditory cortex through the medical geniculate nucleus. Left side shows how a branch from the brainstem relay nuclei contact the reticular brainstem formation, which in turns activtes the medial septal nucleus. The medial septal nucleus cholinergic input acts in the hippocampus to help filter all the sensory information from the cortex, including auditory cortex, that is funneled to it through the Superior Temporal Gyrus.

Figure 2

Dysfunctions in auditory sensory processing in schizophrenia. A. Representative tracing of the P50 sensory gating deficit in schizophrenia. Voltage in microvolts is shown on the vertical axis, time in milliseconds after each stimulus is shown on the horizontal. The response to the first stimulus is solid land the response to the second is dashed. The second response is less inhibited in the schizophrenia patient. B. Brain circuits responsible for sensory processing in the neocortex or hippocampus. AMPA-type glutamate receptors are responsible for the excitatoy transmission of sensory input to the pyramidal cells, where integration into images and memory occurs. Inhibitory feedback to help the pyramidal cells’ selective focusing of their response cccurs through GABA transmission from inhibitory interneurons. Interneuron function is modulated by α7-nicotinic cholinergic receptors that are activated by subcortical midbrain cholinergic pathways, which convey sensory gating responses from subcortical mechanims, such as those shown in Figure 1, and NMDA-type glutamate receptors that convey information about unusual or mismatched stimulus characteristics. C. Paradigm for mismatch negativity (MMN) generation; the detection of the deviant tone generates the MMN. Diminished MMN is seen in schizophrenia regardless of whether the tone is deviant in duration, pitch or frequency, or intensity from a train of otherwise identical stimuli. D. Topographical distribution of MMN deficits in schizophrenia (65).

Figure 3

Visual event-related potential deficits in schizophrenia in response to low versus high spatial frequency stimuli in schizophrenia. Top panel shows example of these visual stimuli, which appear as waves. The C1 component of the response at 94 msec is followed by the P1 at 138 msec. The arrows show lower amplitudes of both early components in the patients at low frequency stimulation. The lower frequency stimuli preferentially activate the neuronal mechamisms that help draw patients’ attention to more important features of their surroundings (from 90)