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Cortical Folding May Predict Antipsychotic Drug Response

August 28, 2013. Examining the folds of the brain's outer layer, the cortex, provides clues about which patients with first-episode psychosis will respond well to antipsychotics, reports a new study published online August 14, 2013, in JAMA Psychiatry. Lena Palaniyappan of the U.K.'s University of Nottingham and colleagues found that non-responders (those whose symptoms did not improve with subsequent antipsychotic treatment) showed less cortical gyrification in several brain regions than did treatment responders.

Although many patients with first-episode psychosis (FEP) experience symptom reduction and even remission following antipsychotic treatment, symptoms remain for some. Early treatment response is one of the best predictors of functional outcome (Emsley et al., 2007), yet determining just who will respond well remains a challenge. Several neuroimaging studies have probed the link between treatment response and brain structure in psychosis. For example, alterations in cortical gyrification are present after obstetric complications, a well-replicated risk factor for schizophrenia, and are also associated with treatment-resistant psychotic symptoms (Cachia et al., 2008).

In the current study, Palaniyappan and colleagues examined gyrification across the entire cortical surface using magnetic resonance imaging (MRI). FEP patients were scanned as soon as possible after their first clinical contact to allow for minimal antipsychotic drug exposure. The severity of psychotic symptoms was assessed on the day of the brain scan and again after 12 weeks of antipsychotic treatment, using the Positive and Negative Syndrome Scale (PANSS).

The researchers used a 3D reconstruction of the cortical surface to compute local measurements of gyrification at thousands of vertices across the surface—termed local gyrification indices—each indicative of the amount of cortex buried within a particular point. Palaniyappan and colleagues found decreased gyrification in 80 FEP patients compared to 46 controls in several cortical regions: the left middle/inferior frontal gyrus, precentral gyrus, and precuneus and the right middle frontal gyrus and inferior parietal region.

Reviewing response to treatment
When the researchers split the patients into two groups—those who responded to subsequent antipsychotic treatment (n = 40) and those who did not (n = 40)—they also found differences in gyrification. Compared to treatment responders, non-responders exhibited reduced cortical folding (or hypogyria) in the insula, superior frontal, and rostral middle frontal regions in the left hemisphere and the inferior and superior temporal cortex in the right hemisphere.

When compared to controls, both responders and non-responders displayed significant hypogyria of the left lingual gyrus. However, while the responders' gyrification looked similar to controls' in all other areas, non-responders had significantly less gyrification than controls did in a number of cortical regions, including the bilateral middle frontal gyrus, the right superior/inferior temporal cortex, angular gyrus, and medial occipital cortex, and the left posterior cingulate and precuneus.

Thus, "…already at illness onset, patients with FEP who subsequently do not respond to treatment have significant cortical folding defects compared with patients who subsequently respond and with healthy controls, while those who go on to respond are virtually indistinguishable from the controls," conclude the authors.

Although methodological differences preclude a direct comparison of the current surface-based approach with previous voxel-based morphometry studies, the authors also noted that their results are broadly consistent with earlier findings of reduced gray matter volume in non-responders (Szeszko et al., 2012).

Delving into diagnosis
As a secondary outcome measure, Palaniyappan and colleagues also measured gyrification as a function of diagnosis. They found that patients with nonaffective psychosis (schizophrenia, schizoaffective disorder, schizophreniform disorder, and psychosis not otherwise specified; n = 56) had reduced gyrification in several brain areas compared to those with affective psychosis (bipolar disorder and major depression with psychosis; n = 24). Because cortical folding develops most rapidly early in life, these results may be consistent with the idea that schizophrenia is characterized by greater neurodevelopmental abnormalities than bipolar disorder or depression.

The researchers found no significant interaction between diagnosis and treatment response. However, responders with nonaffective psychosis had reduced gyrification of the bilateral insula and left medial orbitofrontal, dorsolateral prefrontal, and superior temporal sulci relative to those with affective psychosis, while non-responders did not have a significant difference in gyrification between diagnostic groups. Despite some overlap, the gyrification deficits that were associated with poor treatment response were largely separate from those that characterized nonaffective psychoses.

"Our study provides crucial evidence of neuroimaging markers that can be used early in psychosis to predict prognosis in clinical settings," conclude the authors, adding that early identification of non-responders may lead to alternative, more effective treatment plans for these individuals.—Allison A. Curley.

Reference:
Palaniyappan L, Marques TR, Taylor H, Handley R, Mondelli V, Bonaccorso S, Giordano A, McQueen G, Diforti M, Simmons A, David AS, Pariante CM, Murray RM, Dazzan P. Cortical Folding Defects as Markers of Poor Treatment Response in First-Episode Psychosis. JAMA Psychiatry. 2013 Aug 14. Abstract

 
Comments on News and Primary Papers
Comment by:  Robert B. Zipursky
Submitted 6 September 2013 Posted 6 September 2013

Palaniyappan et al. demonstrated that subjects with a first episode of psychosis (FEP) had a reduction in the extent of cortical gyrification in multiple brain areas compared to healthy comparison subjects. Notably, non-responders showed more prominent hypogyria than responders did in a number of frontal and temporal areas irrespective of whether the underlying diagnosis was of an affective or non-affective psychosis.

Previous studies using structural MRI have established that subjects with FEP have smaller cerebral gray matter volumes (Zipursky et al., 1992) but have left open the question of whether these differences reflect the result of early neurodevelopmental processes that are aberrant versus progressive degenerative losses taking place more proximal to the onset of psychosis. Palaniyappan et al. suggest that measures of cortical gyrification, which is believed to be particularly active during intrauterine growth and early infancy, are more indicative of a developmental than a degenerative process. Their finding that...  Read more


View all comments by Robert B. Zipursky

Comment by:  S. Charles Schulz (Disclosure)
Submitted 6 September 2013 Posted 6 September 2013

This study by Palaniyappan et al. is an excellent step in using neuroscience measures—in this case MRI imaging—to address the important issue of treatment outcomes. As noted by the authors, this is a new way to address outcome in the early phase of psychotic disorders and may be related to the issue of poorer outcome with increased duration of untreated psychosis (DUP). In other words, the literature does show that approximately 25 percent of young people with schizophrenia are not responsive to first-line antipsychotic medication (Agid et al., 2011). Therefore, ways to provide the best treatments sooner can be very helpful in improving outcome.

The authors use an excellent test and examine more than just a single brain area. This newer strategy can lead to much better assessments than earlier work with a single measure. Further, by using MRI measures in the first episode of psychotic illness, they are adding to the initial evaluation of psychotic illness—making sure that there is not some other cause of psychosis.

In...  Read more


View all comments by S. Charles Schulz
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