Advances in neuroimaging, cell biology, and post mortem analysis are starting to explain what happens in the brain of a person who develops schizophrenia. Schizophrenia appears to be a developmental disorder of disrupted neural connection within and between regions of the brain. These disruptions seem to result from genetic predispositions interacting with negative environmental events.
A matter of gray and white
Individuals with schizophrenia have deficits in gray matter and white matter, as illustrated by studies linking auditory hallucinations with brain regions associated with normal hearing (Box).
Gray matter. Magnetic resonance imaging (MRI) indicates that gray matter volume peaks in early adolescence and declines with age. The normal adolescent brain shrinks as inefficient neural connections are pruned away, a process that refines and matures gray matter. In individuals with schizophrenia, this reduction is more aggressive—perhaps because of excessive pruning—and occurs in the time frame when schizophrenia symptoms typically emerge.
Rapoport et al1 documented this process through sequential MRI scans in children with early-onset schizophrenia (mean age 14.5). Compared with age-matched healthy controls, youths with schizophrenia show greater and more rapid gray matter loss during late adolescence (Figure 1).2
Increased density. Reduced neuronal branching and spine formation also likely causes subtle reductions in gray matter volume (Figure 2). The resulting lack of dendritic connectivity may produce cognitive impairments and negative symptoms seen in schizophrenia.
Postmortem studies of gray matter cells show increased neuron density in patients with schizophrenia when compared with controls.3 Patients with schizophrenia have the same number of neurons as controls, but the neurons are more tightly packed because of reduced cell size, branching, and synapse formation.4
Research over the past decade has revealed schizophrenia to be a neurodegenerative disorder characterized by substantial brain tissue loss during first and subsequent psychotic episodes.5 Neuroimaging studies show that clinical and functional deterioration accompanies progressive loss of cortical gray matter volume and enlargement of cerebral ventricles. Thus, preventing relapses has come to be regarded as critical to long-term schizophrenia management.
Auditory hallucinations appear to emanate from the temporal lobe, the same brain region that processes external sound. Thus, it may be that patients experiencing hallucinations are misidentifying inner speech as coming from an outside source.
Using functional MRI to differentiate brain activity signals associated with hallucinating and nonhallucinating states, Dierks et al21 documented increased activity in auditory cortical gray matter during hallucinations in schizophrenia patients.
Auditory signals make synaptic connections in the thalamus (left) before reaching the auditory cortex. White matter fiber tracts called the arcuate fasciculus (right) connect the auditory cortex in the temporal lobe with Broca’s area in the frontal cortex.
Source: Adapted from reference 2
Using MR diffusion tensor imaging, Hubl et al22 identified white matter changes in the arcuate fasciculus of schizophrenia patients prone to hallucinations, compared with healthy controls and patients who had schizophrenia but not hallucinations.
These findings support the understanding that auditory hallucinations originate from altered connectivity of the same regions that process normal hearing and speech. The schizophrenia patient may perceive external voices from aberrant internal signals.
Figure 1 Rates of gray matter volume loss during adolescence
Youths with early-onset schizophrenia show greater gray matter volume loss during adolescence, compared with normal controls.
Source: Adapted from reference 2
Figure 2 Structural differences between neurons
in patients with schizophrenia and controls
Schizophrenic neurons show reduced soma size, spine formation, and dendritic branching
Source: Adapted from reference 2White matter. Recent research suggests that white matter deficits also may be involved in schizophrenia’s pathophysiology. Studies using diffusion tensor imaging (DTI)—which measures the sum of vectors of water diffusion along axons—have documented white matter impairments in patients with schizophrenia.6
White matter tracks—myelinated axons that transport electrical signals among neurons—connect regions within the cortex and between the cortex and deeper brain structures. Disruption of white matter tracks may degrade signals and confuse neuronal communication.
Myelination. Genetic studies in patients with schizophrenia also have suggested that decreased neuron myelination may play a role in white matter deficits. Hakak et al8 examined more than 6,000 genes using microarray analysis and found only 17 genes were significantly down-regulated in patients with schizophrenia. Of those 17 genes, 6 were related to myelin and 11 showed no pattern.
Oligodendrocytes are glial cells that insulate axons with myelin and allow faster transmission of electrical impulses in the brain. In a postmortem study, Hof et al7 found 7 patients schizophrenia had 28% fewer oligodendrocytes per section of the superior frontal gyrus and 27% less white matter compared with 7 age-matched controls (Figure 3).