Oh, Oh… Psychiatric Descriptions of Mental Illnesses May Not Jibe With Distinct Brain Disorders – Which Appear Common Across Major Mental Illnesses.


“…there is a disconnection between current psychiatric nosology and rapidly emerging biological findings, which  emphasizes the need to look for neurobiological substrates shared across diagnoses.”

“During the past several decades, psychiatry has focused on establishing diagnostic categories based on clinical symptoms. Accordingly, most neuroimaging studies have compared brain structure or function in patients with a single, specific diagnosis with healthy participants. I n turn, even closely related diagnostic categories are rarely compared with each other. Nonetheless, neuroimaging research is suggestive of common neurobiological abnormalities across phenotypically related diagnoses (eg, schizophrenia [SCZ] and bipolar disorder [BPD] or anxiety and depression). These data have also converged on the idea that psychiatric illnesses affect the operation of commonly observed distributed neural circuits. Additionally, genetic analyses have identified common polymorphisms associated with a large range of psychiatric diagnoses,9 and comorbidity between diagnoses is considerably higher than expected by chance.  Thus, there is a disconnection between current psychiatric nosology and rapidly emerging biological findings, which emphasizes the need to look for neurobiological substrates shared across diagnoses.”

In summary, these results suggest that”
– anterior insula and dACC gray matter loss represent a transdiagnostic neural abnormality evident across a wide variety of mental illnesses, most pronounced in psychosis.
– In a contrast of psychotic and nonpsychotic diagnosis groups, we found that the psychotic group had both greater gray matter loss in the medial prefrontal cortex, insula, thalamus, and amygdala , as well as greater increases in striatal gray matter.

We then further subdivided the nonpsychotic diagnosis group into 3 groupings: internalizing (depression [MDD], OCD, and anxiety disorders [ANX]), externalizing (substance use disorders), and BPD…Contrasts between these groups identified clusters in the anterior hippocampus, extending into the amygdala. Specifically, internalizing disorders had greater hippocampal/amygdala gray matter loss than both the externalizing or BPD diagnostic groups. This effect was driven by the MDD group, wherein we found greater hippocampal/amygdala gray matter loss than in the other internalizing…Internalizing disorders show greater gray matter loss in the anterior hippocampus and amygdala when compared with either externalizing or BPD diagnoses. This effect is driven by the major depressive disorder (MDD) group, which shows greater gray matter loss in these regions than the other diagnoses within the internalizing grouping (anxiety disorder [ANX] and obsessive-compulsive disorder [OCD]).

Among other functions, activity in the dACC and anterior insula is thought to signal events that deviate from expectations, which is then used to drive adaptive behavioral control. Executive dysfunction is an important transdiagnostic domain of disrupted adaptive control in mental illness. Altered structural integrity of the common gray matter loss regions may predict performance on cognitive tests of executive function….Because these tasks assessed overlapping cognitive domains and because performance data are partially correlated across tasks, we conducted a data-reduction step using a principal components analysis. This resulted in the identification of 3 principal components, which reflected general executive functioning (task switching, interference, and working memory), the specific domain of sustained attention, and combined general cognitive and performance speed (simple reaction time and finger tapping), consistent with identification of an overriding executive function factor in latent variable analyses of cognitive performance data.

…lower gray matter across the 3 common gray matter loss regions still predicted worse performance in terms of general executive function with a similar-direction trend for sustained attention, but no effect on general cognitive and performance speed. Gray matter volume in the primary visual cortex, a control region, was not related to any of the performance measures. These results suggest that lower gray matter in the common gray matter loss regions (ie, more patient-like regional volume) is associated with poorer executive functioning but not general aspects of task performance.

Based on a principal components analysis, cognitive test performance was reduced to 3 components: general executive function:
– the specific domain of sustained attention
– general cognitive performance
– performance speed.

Lower voxel-based morphometry–measured gray matter volume in these regions is associated with worse executive functioning
(A) and a trend for worse sustained attention
(B) but not general performance
(C) speed

In this study, we identified a transdiagnostic pattern of gray matter loss in the anterior insula and dACC across psychiatric patients, reflecting volumetric change within an interconnected network. Follow-up analyses in healthy participants suggest that decreased gray matter in these regions is associated with worse executive functioning. In contrast to this shared neural substrate, diagnosis-specific effects were found only for SCZ and depression. Secondary analyses also suggest that these findings are likely not due to medication effects or the presence of a common comorbid diagnosis across our groups.

Cognitive symptoms are part of the diagnostic criteria for many (but not all) psychiatric diagnoses. Our connection of executive functioning to integrity of a well-established brain network that is perturbed across a broad range of psychiatric diagnoses helps ground a transdiagnostic understanding of mental illness in a context suggestive of common neural mechanisms for disease etiology and/or expression. Executive dysfunction also predicts socio-occupational impairment, a central problem in the lives of many patients with psychiatric illness. In light of these associations, it may be that the common gray matter loss in the anterior insula and dACC accounts for this aspect of dysfunction in psychiatric disorders and perhaps less so diagnosis-specific symptoms.

While our data did not include tests of emotional processing, there may also be a relationship between the volumes of these regions and emotional perturbations, given the role of the anterior insula and dACC in emotional processing and their abnormal activation during affective tasks in at least some of the assessed disorders. Additional emotion-related abnormalities in individuals with decreased anterior insula and dACC gray matter would only further compound their functional impairment. Moreover, graph theoretical work with RS data suggests that there may even be 2 adjacent but functionally distinct insula-dACC networks, one potentially more involved in task control while the other in salience processing.

Convergent data also come from work on neurodegenerative disorders. Specific dementia syndromes have been related to regionally specific gray matter loss in well-described brain networks. Of these, the anterior insula and dACC have been implicated in behavioral variant frontotemporal dementia, the most psychiatric like of dementia syndromes, which can be mistaken for a psychiatric disorder early in its course.

Available evidence in SCZ and posttraumatic stress disorder suggests that insula and dACC gray matter loss may reflect the illness itself rather than a risk state. In SCZ, volume in these regions decreases with psychosis onset relative to individuals in a high-risk state. Decreased insula or dACC volume is seen in individuals with recent-onset posttraumatic stress disorder, but not the twin of patients with posttraumatic stress disorder, who would carry their genetic risk but not have been exposed to trauma. However, there may be certain risk states in which insula/dACC volumes are reduced, such as childhood maltreatment, which is a risk factor for most psychiatric diagnoses.

…In meta-analytically summarizing a more complete spectrum of psychopathology across the entire brain, our findings emphasized the biological commonalities that may have been underappreciated in prior work. Indeed, our only diagnosis-specific findings are in the association of decreased gray matter volumes with MDD84 and association of SCZ with a combination of decreased medial prefrontal, medial temporal, and thalamic gray matter and increased striatal gray matter. The lack of an effect of comorbid disorder (which may otherwise reflect common neurobiology) may be partly owing to the fact that many investigators may have recruited more clinically pure populations.

In light of the common neurobiological changes observed here, which are greatest in the disorder that is most disruptive to functioning (ie, SCZ), future work can focus on determining which aspect of the course of mental illnesses insula and dACC gray matter loss best represent…

Our findings suggest that a general mapping exists between a broad range of symptoms and the integrity of an anterior insula/dACC–based network across a wide variety of neuropsychiatric illnesses. These results do not imply that phenotypic differences between diagnoses are negligible. Rather, they provide an organizing model that emphasizes the import of shared endophenotypes across psychopathology, which is not currently an explicit component of psychiatric nosology. This transdiagnostic perspective is consistent, however, with newer dimensional models such as the National Institute of Mental Health’s Research Domain Criteria Project. Although this shared neural substrate suggests common brain structural changes at some level, it is likely that these changes reflect a diverse set of etiologies. Nonetheless, the fact that common structural changes are seen despite potentially differing etiologies raises the possibility that some interventions that target the anterior insula and dACC may prove of broad use across psychopathology.


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