As part of our ongoing coverage of the 2009 International Congress on Schizophrenia Research (ICOSR), 28 March to 1 April 2009, in San Diego, California, we bring you a meeting missive from researcher C. Anthony Altar, NeuroDrug Consulting.
13 May 2009. Way back in time, during the 1999 ICOSR in Santa Fe, New Mexico, poster reports of small decreases in brain area volumes and ventricular enlargement in schizophrenia were an eye-opener for this author and other attendees. That made for an exciting meeting as neurology and psychiatry collided. Five International Congresses and 10 years later, the 30 March 2009 symposium, "New Perspectives on Progression of Brain Abnormalities in Psychosis," reinforced these findings and elaborated upon brain loss in a number of dimensions, such as decreases in cortical thickness and gray and white matter losses, which are age-dependent and at least twice as great in schizophrenia patients as in control subjects.
Robert McCarley, Harvard University, described post-onset progression of brain abnormalities 1.5 years after the first schizophrenia episode. Remarkably, 7-10 percent increases in CSF/ventricular volume developed in this brief period. That period must be disproportionately severe for ventricular swelling, which might represent a sensitive biomarker, or an etiologic clue, for schizophrenia.
Interestingly, bipolar patients showed a 4 percent increase in neocortical gray matter slightly after disease onset. This increase may be due to medication, since patients who partially took their meds showed only a 2.5 percent increase, and gray matter loss was slightly greater in medication-non-compliant schizophrenia patients. So why not give valproate or other mood stabilizers to all psychotic patients? As McCarley described, the lack of correlation between the Brief Psychiatric Rating Scale (BPRS) and the 5 to 15 percent range of gray matter losses does not predict a clinical benefit from lessening gray matter loss.
The subgenual subdivision of the anterior cingulate cortex was the brain area most consistently atrophied in bipolar disease, while in schizophrenia, atrophy occurred throughout the anterior cingulate, both in subdivisions considered "affective" and "cognitive."
An 8-9 percent loss in gray matter over 1.5 years was found in the left temporal gyri in schizophrenia, with cortical atrophy predominant in the inferior and middle frontal gyri, the superior temporal gyrus (STG), left cingulate cortex, and the insula. Changes in the 30-item Mini-Mental Status Examination (MMSE) were most strongly correlated (+0.53) with changes in the left or right middle and inferior frontal gyrus. Decreases in volumes of bilateral Heschl’s gyri were correlated with worsening of hallucinatory behavior (r = +0.6; p <0.001), and also with thinking disturbance and unusual thought content. Negative symptoms evaluated with BPRS were correlated with atrophy in left and right inferior frontal gyrus and in the insula (r = +0.8).
Many of the atrophied regions are hyperactive during hallucinations, McCarley said, possibly consistent with excessive glutamate signaling and a longer-term neurotoxic mechanism that produces atrophy.
Similar to McCarley, Hilleke Hulshoff Pol, University Medical Center, Utrecht, showed that the frontal and temporal cerebral cortices suffer the biggest decreases in schizophrenia. Similar volume losses do occur after about age 35 in healthy subjects, but in schizophrenia, Pol reported that these regions have been atrophying since age 25 and at a rate of about 2.5 ml/year. Gray matter losses accelerate to about 5 ml/year by age 70 in schizophrenia, and less in controls. White matter increases occur until midlife in schizophrenia, and then decrease. These losses exceeded those of healthy controls, but their etiology remains unknown.
High-resolution spatial measures of cortical thickness showed decreases over time in schizophrenia that were up to 10 times as great as in control subjects. The greatest losses were in the lateral neocortex, such as the temporal pole, occipital gyrus, left central gyrus, inferior frontal sulcus, post middle temporal gyrus, cuneus, and lingual sulcus. As McCarley had found, the poorer the functioning of the patients, the bigger were the losses over time.
Like the above-mentioned benefit of drugs in bipolar disease, Pol found that the higher the atypical dose, the smaller the loss in cortical thickness. This was also shown in a sub-analysis study for clozapine alone. However, the higher clinical doses of typical antipsychotics were associated with the greatest losses in cortical thickness. It was not clear how differences in socio-economic status, nutrition, or related health factors account for differences between those getting the inexpensive typical agents versus the more costly atypicals.
These results are in good agreement with a meta-analysis Pol conducted of six postmortem studies, in which patients showed a 0.5 percent brain mass loss/year, compared to only 0.2 percent brain loss/year for controls, resulting in 3 percent (70 ml) loss after 20 years for patients versus 1.5 percent (35 ml) for controls.
It appears that the shrinking superior temporal gyrus (STG) is a hot spot for converting to schizophrenia. Christos Pantelis, University of Melbourne, looked at the earliest stages of schizophrenia with a focus on the frontal cortex and STG. Losses here may have a relationship with disorders of language, hallucinations, and delusions, but no studies have examined the STG in non-psychotic individuals. Among individuals at "ultra high risk" for schizophrenia (UHR), 41 percent converted to psychosis by age ~20 years. They showed decreases in STG after the onset of illness but not at first examination, and these decreases correlated with the extent of delusions. Those who did not convert did not show decreases in STG mass. That was impressive.
In summary, these three presentations added considerable support for the enhanced and early loss in the frontal and superior temporal gyri, the anterior cingulate, and Heschl’s gyri in schizophrenia.
A retraction of gray matter away from the skull was apparent during a four-year longitudinal study of normal adults (Sun et al., 2008). Pantelis showed with a subtraction image that enhanced shrinking is prominent in the frontal lobes in schizophrenia, and that this enhanced shrinking occurs along much of the rostral half of the cortex.
The STG is divided into areas most prone to atrophy in schizophrenia: Heschl’s gyrus, which is primary auditory cortex; planum temporale (PT), part of the secondary auditory cortex; and the temporal pole, the most anterior portion of STG. It is likely that auditory hallucinations may result from this atrophy of important auditory areas of the brain, according to Pantelis.
Nitin Gogtay of NIMH published the highly impressive fMRI study on the cortical thinning that occurs from age four to 21 in humans (Gogtay et al., 2004). He discussed progressive gray and white matter abnormalities in childhood-onset schizophrenia (COS; before age 12). COS is, fortunately, rare (one in 40,000). Between ages 12 and 16, these children have a profound (p <0.001 to p = 0.00002) gray matter loss. By age 16, losses are greatest relative to normals, and are most prominent in parietal and temporal, prefrontal, and occipital areas, up to 10-fold more than in normal development.
In his presentation, Gogtay asked, and answered, five questions:
1. Does cortical thinning in COS continue with age? Answer: It clearly cannot do so in a constant manner. Greenstein et al., 2006, found that by the time COS children are 24 years old, further gray matter loss is limited to prefrontal and temporal regions after considerable losses have occurred in superior parietal areas.
2. What is the contribution of the heavy medication status of these children? Answer: Probably little, since patients with the alternative diagnosis of childhood psychosis/not otherwise specified (NOS) also get lots of medications from an early age, but do not go on to develop schizophrenia, and show very little—maybe even less—gray matter loss than healthy controls. Gogtay and colleagues found that a group of 32 COS children on clozapine had thinner cortices than 12 on olanzapine; the rate of loss from age 12 to 23 did not differ (same slope of decreases).
3. Is cortical atrophy genetically influenced? Answer: Maybe. The COMT gene val allele is associated with greater COMT enzyme stability, lower IQ, and poorer cognition. Healthy subjects with the val-val allele have more gray matter thickness decreases over time than val-met or met-met Gogtay et al., 2007. A study that Gogtay et al. conducted with the Weinberger/Straub group at NIMH also showed a positive, pairwise association between COS and three SNPs in the 5' upstream region of GAD1 (GAD67) and an association with increased frontal gray matter loss (Addington et al., 2005). This writer wonders whether patients with COMT-val-val and the GAD1 SNPs show the greatest neocortical atrophy.
4. Are trajectory differences limited to the cortex? Answer: No. COS patients show significantly steeper slopes of loss in all subregions of the cerebellum versus healthy controls.
5. Could the gray matter loss be due to white matter encroachment? Answer:
No. Both white and gray matter growth are highly compromised, based on analysis of 12 COS subjects (studied between ages 12-18). The annual growth rate of cortical white matter was less in COS subjects versus controls.
Our own International Congress on Schizophrenia Research organizer, Carol Tamminga, University of Texas, Southwestern, showed with fMRI that regional cerebral blood flow (rCBF) is increased in the anterior hippocampus of schizophrenia patients off medication, and that antipsychotic drugs reduce perfusion to normal levels in the hippocampus. Tamminga's group has found that hippocampal activation in response to novel pictures is markedly lower in untreated patients versus controls, but reaches normal levels with medication. A new method employing a contrast agent provided remarkably high-resolution MRI images; one had the feeling of looking at a brain tissue section rather than an MRI image. This additional method, in two schizophrenia subjects, showed an increased fMRI signal in CA3, and normalization with antipsychotic drugs.
The model that Tamminga and colleagues propose is that in schizophrenia, there is lower dentate granule neuron communication with the CA3 subfield of the anterior hippocampus. This elevates metabolic activity of the terminal areas innervated by the dentate neurons. This is consistent with decreases in metabolic gene expression in the dentate granule neurons of schizophrenia cases (Altar et al., 2005).—C. Anthony Altar.