Abnormal Cerebellar Volume in Patients with Remitted Major Depression with Persistent Cognitive Deficits.

Cerebellar involvement in major depressive disorder (MDD) has been demonstrated by a growing number of studies, but it is unknown whether cognitive functioning in depressed individuals is related to cerebellar gray matter volume (GMV) abnormalities. Impaired attention and executive dysfunction are characteristic cognitive deficits in MDD, and critically, they often persist despite remission of mood symptoms. In this study, we investigated cerebellar GMV in patients with remitted MDD (rMDD) that showed persistent cognitive impairment. We applied cerebellum-optimized voxel-based morphometry in 37 patients with rMDD and with cognitive deficits, in 12 patients with rMDD and without cognitive deficits, and in 36 healthy controls (HC). Compared with HC, rMDD patients with cognitive deficits had lower GMV in left area VIIA, crus II, and in vermal area VIIB. In patients with rMDD, regression analyses demonstrated significant associations between GMV reductions in both regions and impaired attention and executive dysfunction. Compared with HC, patients without cognitive deficits showed increased GMV in bilateral area VIIIB. This study supports cerebellar contributions to the cognitive dimension of MDD. The data also point towards cerebellar area VII as a potential target for non-invasive brain stimulation to treat cognitive deficits related to MDD.

Abnormal cerebellar volume in somatic vs. non-somatic delusional disorders.

BACKGROUND: There is abundant evidence for cerebellar involvement in schizophrenia, where the cerebellum has been suggested to contribute to cognitive, affective and motor dysfunction. More recently, specific cerebellar regions have also been associated with psychotic symptoms, particularly with auditory verbal hallucinations. In contrast, little is known about cerebellar contributions to delusions, and even less is known about whether cerebellar involvement differs by delusional content. METHODS: Using structural magnetic resonance imaging at 1.0 T together with cerebellum-optimized segmentation techniques, we investigated gray matter volume (GMV) in 14 patients with somatic-type delusional disorder (S-DD), 18 patients with non-somatic delusional disorder (NS-DD) and 18 patients with schizophrenia (SZ) with persistent non-somatic delusions. A total of 32 healthy controls (HC) were included. Between-group comparisons were adjusted for age, gender, chlorpromazine equivalents and illness duration. RESULTS: Compared to HC, S-DD patients showed decreased GMV in left lobule VIIIa. In addition, S-DD patients showed decreased GMV in lobule V and increased GMV in bilateral lobule VIIa/crus II compared to NS-DD. Patients with SZ showed increased GMV in right lobule VI and VIIa/crus I compared to HC. Significant differences between HC and NS-DD were not found. CONCLUSIONS: The data support the notion of cerebellar dysfunction in psychotic disorders. Distinct cerebellar deficits, predominantly linked to sensorimotor processing, may be detected in delusional disorders presenting with predominantly somatic content.

Cognitive remediation therapy modulates intrinsic neural activity in patients with major depression.

BACKGROUND: Cognitive impairment is a core feature of major depressive disorder (MDD). Cognitive remediation may improve cognition in MDD, yet so far, the underlying neural mechanisms are unclear. This study investigated changes in intrinsic neural activity in MDD after a cognitive remediation trial. METHODS: In a longitudinal design, 20 patients with MDD and pronounced cognitive deficits and 18 healthy controls (HC) were examined using resting-state functional magnetic resonance imaging. MDD patients received structured cognitive remediation therapy (CRT) over 5 weeks. The whole-brain fractional amplitude of low-frequency fluctuations was computed before the first and after the last training session. Univariate methods were used to address regionally-specific effects, and a multivariate data analysis strategy was employed to investigate functional network strength (FNS). RESULTS: MDD patients significantly improved in cognitive function after CRT. Baseline comparisons revealed increased right caudate activity and reduced activity in the left frontal cortex, parietal lobule, insula, and precuneus in MDD compared to HC. In patients, reduced FNS was found in a bilateral prefrontal system at baseline (p < 0.05, uncorrected). In MDD, intrinsic neural activity increased in right inferior frontal gyrus after CRT (p < 0.05, small volume corrected). Left inferior parietal lobule, left insula, left precuneus, and right caudate activity showed associations with cognitive improvement (p < 0.05, uncorrected). Prefrontal network strength increased in patients after CRT, but this increase was not associated with improved cognitive performance. CONCLUSIONS: Our findings support the role of intrinsic neural activity of the prefrontal cortex as a possible mediator of cognitive improvement following CRT in MDD.

Exploring cortical predictors of clinical response to electroconvulsive therapy in major depression.

Electroconvulsive therapy (ECT) is a rapid and highly effective treatment option for treatment-resistant major depressive disorder (TRD). The neural mechanisms underlying such beneficial effects are poorly understood. Exploring associations between changes of brain structure and clinical response is crucial for understanding ECT mechanisms of action and relevant for the validation of potential biomarkers that can facilitate the prediction of ECT efficacy. The aim of this explorative study was to identify cortical predictors of clinical response in TRD patients treated with ECT. We longitudinally investigated 12 TRD patients before and after ECT. Twelve matched healthy controls were studied cross sectionally. Demographical, clinical, and structural magnetic resonance imaging data at 3 T and multiple cortical markers derived from surface-based morphometry (SBM) analyses were considered. Multiple regression models were computed to identify predictors of clinical response to ECT, as reflected by Hamilton Depression Rating Scale (HAMD) score changes. Symptom severity differences pre-post-ECT were predicted by models including demographic data, clinical data and SBM of frontal, cingulate, and entorhinal structures. Using all-subsets regression, a model comprising HAMD score at baseline and cortical thickness of the left rostral anterior cingulate gyrus explained most variance in the data (multiple R2 = 0.82). The data suggest that SBM provides powerful measures for identifying biomarkers for ECT response in TRD. Rostral anterior cingulate thickness and HAMD score at baseline showed the greatest predictive power of clinical response, in contrast to cortical complexity, cortical gyrification, or demographical data.

Aberrant cortical neurodevelopment in major depressive disorder.

BACKGROUND: There is strong neuroimaging evidence that cortical alterations represent a core pathophysiological feature of major depressive disorder (MDD). Differential contributions of cortical features of neurodevelopmental origin, which may distinctly contribute to MDD vulnerability, disease-onset, or symptom expression, are unclear at present. METHODS: We investigated distinct markers of cortical neurodevelopment, i.e. local cortical gyrification (LGI) and thickness (CT) in patients with MDD (n = 38) and healthy controls (HC, n = 22) using 3 T structural magnetic resonance imaging data and surface-based data analysis techniques. CT and LGI were computed using the Computational Anatomy Toolbox (CAT12). Analyses were performed for the entire cortical surface followed by a complementary regions-of-interest approach. RESULTS: MDD patients showed significantly greater LGI in frontal, cingulate, parietal, temporal, and occipital regions compared to HC (FDR-corrected at p < 0.05 using threshold-free cluster enhancement). No significant differences of CT were found. In the MDD-group, correlations were found between duration of illness in years and number of depressive episodes and LGI of frontal, temporal, and parietal regions (p < 0.05). LIMITATIONS: Main limitations are the relatively modest sample size and a cross-sectional study design. We did not control for early environmental factors potentially influencing neurodevelopment, such as childhood trauma. We report associations uncorrected for multiple comparisons. CONCLUSIONS: The data suggest different local trajectories of cortical change in MDD. In addition, our data support the notion that aberrant cortical development may serve as a vulnerability marker of MDD, as well as a potential predictor of disease course.

Cerebellar Contributions to Major Depression.

Extending beyond the motor domain, the cerebellum is involved in various aspects of cognition and affect. Multidisciplinary evidence has demonstrated topographic organization of higher-order cognitive functions within the cerebellum. We here review recent neuroimaging research that indicates cerebellar contributions to major depressive disorder (MDD). At the structural level, increased volume of lobule IX has been demonstrated in MDD patients, independent of acute or remitted disease state. Successful treatment with electroconvulsive therapy has been associated with increased lobule VIIA volume in depressed patients. At the functional level, connectivity analyses have shown reduced cerebro-cerebellar coupling of lobules VI and VIIA/B with prefrontal, posterior parietal, and limbic regions in patients with MDD. As a limitation, most of this evidence is based on smaller patient samples with incomplete phenotypic and neuropsychological characterization and with heterogenous medication. Some studies did not apply cerebellum-optimized data analysis protocols. Taken together, MDD pathophysiology affects distinct subregions of the cerebellum that communicate with cortical networks subserving cognitive and self-referential processing. This mini-review synthesizes research evidence from cerebellar structural and functional neuroimaging in depression, and provides future perspectives for neuroimaging of cerebellar contributions to MDD.

Common and distinct patterns of abnormal cortical gyrification in major depression and borderline personality disorder.

Abnormal gray matter volume has been consistently reported in patients with major depressive disorder (MDD), but markers of cortical neurodevelopment have been rarely investigated. Also, it is unclear whether there exist common versus distinct spatial patterns of abnormal cortical development across different disorders presenting with negative emotions and deficient affective regulation. In this study, we used structural MRI at 3T to investigate the local gyrification index (LGI), a marker of fetal/infant neurodevelopment, in adult female patients with MDD (n = 22), in adult female patients with borderline personality disorder (BPD) (n = 17), and in controls (n = 22). Reduced cortical folding of the precuneus, the superior parietal gyrus and the parahippocampal gyrus was found in both MDD and BPD patients when compared to controls (p < 0.05, cluster-wise probability [CWP] corrected). MDD patients showed additional hypogyrification of the middle frontal gyrus and the fusiform gyrus when compared to both controls and BPD patients (p < 0.05, CWP corrected). In MDD patients, lower LGI of prefrontal regions was significantly associated with the age of disease onset and with the number of depressive episodes. In BPD patients, lower LGI of orbitofrontal regions was associated with impulsivity. Our findings suggest abnormal early cortical development in MDD, affecting brain regions that have been frequently implied in MDD pathophysiology. However, LGI abnormalities may not be specific for MDD, since MDD and BPD patients also exhibited common patterns of hypogyrification. Hypogyrification of cortical regions associated with higher-order cognition appears to be most pronounced in MDD. Abnormal early cortical neurodevelopment may mediate vulnerability to disorders of emotion.

Aberrant resting-state cerebellar blood flow in major depression.

BACKGROUND: Abnormal cortical cerebral blood flow and gray matter volume have been frequently reported in patients with major depressive disorder (MDD). In contrast, although the role of the cerebellum in MDD pathophysiology has attracted considerable interest more recently, studies investigating both functional and structural aspects of cerebellar integrity are scarce. METHODS: In this study, we used structural and functional magnetic resonance imaging (MRI) to investigate cerebellar volume and regional cerebellar blood flow (rCBF) at rest in clinically acute MDD patients (n = 22) and healthy controls (n = 18). We acquired high-resolution structural images at 3 T together with perfusion images obtained with continuous arterial spin labeling. Cerebellar structure and function were investigated using cerebellum-optimized analysis techniques. RESULTS: Markedly increased rCBF was found in bilateral cerebellar areas VIIa and VIIIb (p < 0.05 family-wise-error [FWE] corrected). Significant differences in cerebellar volume between patients and controls were not found (p < 0.05, FWE-corrected). Left cerebellar area VIIa perfusion was significantly associated with depressive symptoms, as measured by the Hamilton Depression Rating Scale. LIMITATIONS: Potential limitations of this study include the modest sample size, the cross-sectional design, the lack of task-related imaging and the heterogeneity of drug treatment. CONCLUSIONS: The data suggest contributions of "affective" cerebellar regions to MDD pathophysiology and symptom expression. While cerebellar perfusion at rest is compromised in MDD, cerebellar volume seems to be less affected.

Cerebellar volume change in response to electroconvulsive therapy in patients with major depression.

Electroconvulsive therapy (ECT) is remarkably effective in severe major depressive disorder (MDD). Growing evidence has accumulated for brain structural and functional changes in response to ECT, primarily within cortico-limbic regions that have been considered in current neurobiological models of MDD. Despite increasing evidence for important cerebellar contributions to affective, cognitive and attentional processes, investigations on cerebellar effects of ECT in depression are yet lacking. In this study, using cerebellum-optimized voxel-based analysis methods, we investigated cerebellar volume in 12 MDD patients who received right-sided unilateral ECT. 16 healthy controls (HC) were included. Structural MRI data was acquired before and after ECT and controls were scanned once. Baseline structural differences in MDD compared to HC were located within the "cognitive cerebellum" and remained unchanged with intervention. ECT led to gray matter volume increase of left cerebellar area VIIa crus I, a region ascribed to the "affective/limbic cerebellum". The effects of ECT on cerebellar structure correlated with overall symptom relief. These findings provide preliminary evidence that structural change of the cerebellum in response to ECT may be related to the treatment's antidepressant effects.

Abnormal cerebellar volume in acute and remitted major depression.

Abnormal cortical volume is well-documented in patients with major depressive disorder (MDD), but cerebellar findings have been heterogeneous. It is unclear whether abnormal cerebellar structure relates to disease state or medication. In this study, using structural MRI, we investigated cerebellar volume in clinically acute (with and without psychotropic treatment) and remitted MDD patients. High-resolution structural MRI data at 3T were obtained from acute medicated (n=29), acute unmedicated (n=14) and remitted patients (n=16). Data from 29 healthy controls were used for comparison purposes. Cerebellar volume was investigated using cerebellum-optimized voxel-based analysis methods. Patients with an acute MDD episode showed increased volume of left cerebellar area IX, and this was true for both medicated and unmedicated individuals (p<0.05 cluster-corrected). Remitted patients exhibited bilaterally increased area IX volume. In remitted, but not in acutely ill patients, area IX volume was significantly associated with measures of depression severity, as assessed by the Hamilton Depression Rating Scale (HAMD). In addition, area IX volume in remitted patients was significantly related to the duration of antidepressant treatment. In acutely ill patients, no significant relationships were established using clinical variables, such as HAMD, illness or treatment duration and number of depressive episodes. The data suggest that cerebellar area IX, a non-motor region that belongs to a large-scale brain functional network with known relevance to core depressive symptom expression, exhibits abnormal volume in patients independent of clinical severity or medication. Thus, the data imply a possible trait marker of the disorder. However, given bilaterality and an association with clinical scores at least in remitted patients, the current findings raise the possibility that cerebellar volume may be reflective of successful treatment as well.

Common and distinct structural network abnormalities in major depressive disorder and borderline personality disorder.

Major depressive disorder (MDD) and borderline personality disorder (BPD) show substantial overlap in both affective symptom expression and in regional brain volume reduction. To address the specificity of structural brain change for the respective diagnostic category, we investigated structural networks in MDD and BPD to identify shared and distinct patterns of abnormal brain volume associated with these phenotypically related disorders. Using magnetic resonance imaging at 3 T, we studied 22 females with MDD, 17 females with BPD and without comorbid posttraumatic stress disorder, and 22 age-matched female healthy controls. We used "source-based morphometry" (SBM) to investigate naturally grouping patterns of gray matter volume variation (i.e. "structural networks") and the magnitude of their expression between groups. SBM identified three distinct structural networks which showed a significant group effect (p b 0.05, FDR-corrected). A bilateral frontostriatal network showed reduced volume in MDD compared to both controls and BPD patients. A medial temporal/medial frontal network was found to be significantly reduced in BPD compared to both controls and MDD patients. Decreased cingulate and lateral prefrontal volume was found in both MDD and BPD when compared to healthy individuals. In MDD significant relationships were found between depressive symptoms and a cingulate/lateral prefrontal structural pattern. In contrast, overall BPD symptoms and impulsivity scores were significantly associated with medial temporal/medial frontal network volume. The data suggest both distinct and common patterns of abnormal brain volume in MDD and BPD. Alterations of distinct structural networks differentially modulate clinical symptom expression in these disorders.

Specificity of abnormal brain volume in major depressive disorder: a comparison with borderline personality disorder.

BACKGROUND: Abnormal brain volume has been frequently demonstrated in major depressive disorder (MDD). It is unclear if these findings are specific for MDD since aberrant brain structure is also present in disorders with depressive comorbidity and affective dysregulation, such as borderline personality disorder (BPD). In this transdiagnostic study, we aimed to investigate if regional brain volume loss differentiates between MDD and BPD. Further, we tested for associations between brain volume and clinical variables within and between diagnostic groups. METHODS: 22 Females with a DSM-IV diagnosis of MDD, 17 females with a DSM-IV diagnosis of BPD and without comorbid posttraumatic stress disorder, and 22 age-matched female healthy controls (HC) were investigated using magnetic resonance imaging. High-resolution structural data were analyzed using voxel-based morphometry. RESULTS: A significant (p<0.05, cluster-corrected) volume decrease of the anterior cingulate cortex (ACC) was found in MDD compared to HC, as opposed to volume decreases of the amygdala in BPD compared to both HC and MDD. Sensitivity and specificity of regional gray matter volume for a diagnosis of MDD were modest to fair. Amygdala volume was related to depressive symptoms across the entire patient sample. LIMITATIONS: Potential limitations of this study include the modest sample size and the heterogeneous psychotropic drug treatment. CONCLUSIONS: ACC volume reduction is more pronounced in MDD with an intermediate degree of volume loss in BPD compared to HC. In contrast, amygdala volume loss is more pronounced in BPD compared to MDD, yet amygdala volume is associated with affective symptom expression in both disorders.

Visual system integrity and cognition in early Huntington's disease.

Posterior cortical volume changes and abnormal visuomotor performance are present in patients with Huntington's disease (HD). However, it is unclear whether posterior cortical volume loss contributes to abnormal neural activity, and whether activity changes predict cognitive dysfunction. Using magnetic resonance imaging (MRI), we investigated brain structure and visual network activity at rest in patients with early HD (n = 20) and healthy controls (n = 20). The symbol digit modalities test (SDMT) and subtests of the Visual Object and Space Perception Battery were completed offline. For functional MRI data, a group independent component analysis was used. Voxel-based morphometry was employed to assess regional brain atrophy, and 'biological parametric mapping' analyses were included to investigate the impact of atrophy on neural activity. Patients showed significantly worse visuomotor and visual object performance than controls. Structural analyses confirmed occipitotemporal atrophy. In patients and controls, two spatiotemporally distinct visual systems were identified. Patients showed decreased activity in the left fusiform cortex, and increased left cerebellar activity. These findings remained stable after correction for brain atrophy. Lower fusiform cortex activity was associated with lower SDMT performance and with higher disease burden scores. These associations were absent when cerebellar function was related to task performance and disease burden. The results of this study suggest that regionally specific functional abnormalities of the visual system can account for the worse visuomotor cognition in HD patients. However, occipital volume changes cannot sufficiently explain abnormal neural function in these patients.

Source-based morphometry reveals distinct patterns of aberrant brain volume in delusional infestation.

Little is known about the neural correlates of delusional infestation (DI), the delusional belief to be infested with pathogens. So far, evidence comes mainly from case reports and case series. We investigated brain morphology in 16 DI patients and 16 healthy controls using structural magnetic resonance imaging and a multivariate data analysis technique, i.e. source-based morphometry (SBM). In addition, we explored differences in brain structure in patient subgroups based on disease aetiology. SBM revealed two patterns exhibiting significantly (p<0.05, Bonferroni-corrected) lower grey and higher white matter volume in DI patients compared to controls. Lower grey matter volume was found in medial prefrontal cortex, anterior cingulate cortex, medial temporal lobe structures (parahippocampus and hippocampus), sensorimotor cortices, bilateral insula and thalamus and inferior parietal regions. Higher white matter volume was found in medial and middle frontal and temporal cortices, left insula and lentiform nucleus. Grey matter volume was abnormal in both "psychiatric" (primary DI and DI associated with an affective disorder) and "organic" DI (DI due to a medical condition). In contrast, aberrant white matter volume was only confirmed for the "organic" DI patient subgroup. These results suggest prefrontal, temporal, parietal, insular, thalamic and striatal dysfunction underlying DI. Moreover, the data suggest that aetiologically distinct presentations of DI share similar patterns of abnormal grey matter volume, whereas aberrant white matter volume appears to be restricted to organic cases.