Ranga Krishnan

Amygdala volume in late-life depression: relationship with age of onset.

OBJECTIVES Depression is common in the elderly population. Although numerous neuroimaging studies have examined depressed elders, there is limited research examining how amygdala volume may be related to depression. DESIGN A cross-sectional examination of amygdala volume comparing elders with and without a diagnosis of major depressive disorder, and between depressed subjects with early and later initial depression onset. SETTING An academic medical center. PARTICIPANTS Ninety-one elderly patients meeting Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria for major depression (54 early-onset depressed and 37 late-onset depressed) and 31 elderly subjects without any psychiatric diagnoses. MEASUREMENTS Amygdala and cerebral volumes were measured using reliable manual tracing methods. RESULTS In models controlling for age, sex, and cerebral volume, there was a significant difference between diagnostic cohorts in amygdala volume bilaterally (left: F[2, 116] = 16.28, p < 0.0001; right: F[2, 116] = 16.28, p < 0.0001). Using least squares mean group analyses, both early- and late-onset depressed subjects exhibited smaller bilateral amygdala volumes than did the nondepressed cohort (all comparisons p < 0.0001), but the two depressed cohorts did not exhibit a statistically significant difference. LIMITATIONS Limitations include missing antidepressant treatment data, recall bias, inability to establish a causal relationship between amygdala size and depression given the cross-sectional nature of the design. CONCLUSIONS Depression in later life is associated with smaller amygdala volumes, regardless of age of initial onset of depression.

Functional evidence implicating a novel TOR1A mutation in idiopathic, late-onset focal dystonia

Background TOR1A encodes a chaperone-like AAA-ATPase whose ΔGAG (ΔE) mutation is responsible for an early onset, generalised dystonia syndrome. Because of the established role of the TOR1A gene in heritable generalised dystonia (DYT1), a potential genetic contribution of TOR1A to the more prevalent and diverse presentations of late onset, focal dystonia has been suggested. Results A novel TOR1A missense mutation (c.613T→A, p.F205I) in a patient with late onset, focal dystonia is reported. The mutation occurs in a highly evolutionarily conserved region encoding the AAA-ATPase domain. Expression assays revealed that expression of F205I or ΔE, but not wildtype TOR1A, produced frequent intracellular inclusions. Conclusions A novel, rare TOR1A variant has been identified in an individual with late onset, focal dystonia and evidence provided that the mutation impairs TOR1A function. Together these findings raise the possibility that this novel TOR1A variant may contribute to the expression of dystonia. In light of these findings, a more comprehensive genetic effort is warranted to identify the role of this and other rare TOR1A variants in the expression of late onset, focal dystonia.

Memory-Prediction Errors and Their Consequences in Schizophrenia

Cognitive deficits play a central role in the onset of schizophrenia. Cognitive impairment precedes the onset of psychosis in at least a subgroup of patients, and accounts for considerable dysfunction. Yet cognitive deficits as currently measured are not significantly related to hallucinations and delusions. Part of this counterintuitive absence of a relationship may be caused by the lack of an organizing principle of cognitive impairment in schizophrenia research. We review literature suggesting that a system of memory-based prediction is central to human perception, thought and action , and forward the notion that many of the symptoms of schizophrenia are a result of a failure of this system.

Full central neurokinin-1 receptor blockade is required for efficacy in depression: evidence from orvepitant clinical studies

Full, persistent blockade of central neurokinin-1 (NK1) receptors may be a potential antidepressant mechanism. The selective NK1 antagonist orvepitant (GW823296) was used to test this hypothesis. A preliminary positron emission tomography study in eight male volunteers drove dose selection for two randomized six week studies in patients with major depressive disorder (MDD). Displacement of central [11C]GR205171 binding indicated that oral orvepitant doses of 30–60 mg/day provided >99% receptor occupancy for ≥24 h. Studies 733 and 833 randomized patients with MDD and 17-item Hamilton Depression Rating Scale (HAM-D)≥22 to double-blind treatment with orvepitant 30 mg/day, orvepitant 60 mg/day or placebo (1:1:1). Primary outcome measure was change from baseline in 17-item HAM-D total score at Week 6 analyzed using mixed models repeated measures. Study 733 (n=328) demonstrated efficacy on the primary endpoint (estimated drug-placebo differences of 30 mg: −2.41, 95% confidence interval (CI) (−4.50 to −0.31) p=0.0245; 60 mg: –2.86, 95% CI (−4.97 to −0.75) p=0.0082). Study 833 (n=345) did not show significance (estimated drug-placebo differences of 30 mg: −1.67, 95% CI (−3.73 to 0.39) p=0.1122; 60 mg: −0.76, 95% CI (−2.85 to 1.32) p=0.4713). The results support the hypothesis that full, long lasting blockade of central NK1 receptors may be an efficacious mechanism for the treatment of MDD.

Neural correlates associated with cognitive decline in late-life depression.

OBJECTIVES Persistent cognitive impairment (PCI) after remission of depressive symptoms is a major adverse outcome of late-life depression (LLD). The purpose of this study was to examine neural substrates associated with PCI in LLD. DESIGN Longitudinal study. SETTING Outpatient depression treatment study at Duke University. PARTICIPANTS Twenty-three patients with LLD completed a 2-year follow-up study, and were in a remitted or partially remitted state at Year 2. METHODS At first entry to the study (Year 0), all participants had a functional magnetic resonance imaging scan while performing an emotional oddball task. For the purpose of this report, the primary functional magnetic resonance imaging outcome was brain activation during target detection, which is a measure of executive function. The Consortium to Establish a Registry for Alzheimers Disease neuropsychological battery was used to assess cognitive status yearly, and the Montgomery-Åsberg Depression Rating Scale was used to assess severity of depression at Year 0 and every 6 months thereafter for 2 years. We investigated changes in brain activation at Year 0 associated with PCI over 2 years. RESULTS Patients with PCI at the 2-year follow-up date had significantly decreased activation at Year 0 in the dorsal anterior cingulate cortex, hippocampus, inferior frontal cortex, and insula compared to non-PCI patients. CONCLUSIONS Our results suggest individuals who have LLD with PCI have decreased activation in the similar neural networks associated with the development of Alzheimer disease among nondepressed individuals. Measuring neural activity in these regions in individuals with LLD may help identify patients at-risk for cognitive impairment.

Disrupted salience network functional connectivity and white-matter microstructure in persons at risk for psychosis: findings from the LYRIKS study.

Background Salience network (SN) dysconnectivity has been hypothesized to contribute to schizophrenia. Nevertheless, little is known about the functional and structural dysconnectivity of SN in subjects at risk for psychosis. We hypothesized that SN functional and structural connectivity would be disrupted in subjects with At-Risk Mental State (ARMS) and would be associated with symptom severity and disease progression. Method We examined 87 ARMS and 37 healthy participants using both resting-state functional magnetic resonance imaging and diffusion tensor imaging. Group differences in SN functional and structural connectivity were examined using a seed-based approach and tract-based spatial statistics. Subject-level functional connectivity measures and diffusion indices of disrupted regions were correlated with CAARMS scores and compared between ARMS with and without transition to psychosis. Results ARMS subjects exhibited reduced functional connectivity between the left ventral anterior insula and other SN regions. Reduced fractional anisotropy (FA) and axial diffusivity were also found along white-matter tracts in close proximity to regions of disrupted functional connectivity, including frontal-striatal-thalamic circuits and the cingulum. FA measures extracted from these disrupted white-matter regions correlated with individual symptom severity in the ARMS group. Furthermore, functional connectivity between the bilateral insula and FA at the forceps minor were further reduced in subjects who transitioned to psychosis after 2 years. Conclusions Our findings support the insular dysconnectivity of the proximal SN hypothesis in the early stages of psychosis. Further developed, the combined structural and functional SN assays may inform the prognosis of persons at-risk for psychosis.

Large-Scale Network Topology Reveals Heterogeneity in Individuals With at Risk Mental State for Psychosis: Findings From the Longitudinal Youth-at-Risk Study

Emerging evidence demonstrates heterogeneity in clinical outcomes of prodromal psychosis that only a small percentage of at-risk individuals eventually progress to full-blown psychosis. To examine the neurobiological underpinnings of this heterogeneity from a network perspective, we tested whether the early patterns of large-scale brain network topology were associated with risk of developing clinical psychosis. Task-free functional MRI data were acquired from subjects with At Risk Mental State (ARMS) for psychosis and healthy controls (HC). All individuals had no history of drug abuse and were not on antipsychotics. We performed functional connectomics analysis to identify patterns of system-level functional brain dysconnectivity associated with ARMS individuals with different outcomes. In comparison to HC and ARMS who did not transition to psychosis at follow-up (ARMS-NT), ARMS individuals who did (ARMS-T) showed marked brain functional dysconnectivity, characterized by loss of network segregation and disruption of network communities, especially the salience, default, dorsal attention, sensorimotor and limbic networks (P < 0.05 FWE-corrected, Cohens d > 1.00), and was associated with baseline symptom severity. In contrast, we did not observe connectivity differences between ARMS-NT and HC individuals. Taken together, these results suggest a possible large-scale functional brain network topology phenotype related to risk of psychosis transition in ARMS individuals.

Brain-computer-interface-based intervention re-normalizes brain functional network topology in children with attention deficit/hyperactivity disorder

A brain-computer-interface (BCI)-based attention training game system has shown promise for treating attention deficit/hyperactivity disorder (ADHD) children with inattentive symptoms. However, little is known about brain network organizational changes underlying behavior improvement following BCI-based training. To cover this gap, we aimed to examine the topological alterations of large-scale brain functional networks induced by the 8-week BCI-based attention intervention in ADHD boys using resting-state functional magnetic resonance imaging method. Compared to the non-intervention (ADHD-NI) group, the intervention group (ADHD-I) showed greater reduction of inattention symptoms accompanied with differential brain network reorganizations after training. Specifically, the ADHD-NI group had increased functional connectivity (FC) within the salience/ventral attention network (SVN) and increased FC between task-positive networks (including the SVN, dorsal attention (DAN), somatomotor, and executive control network) and subcortical regions; in contrast ADHD-I group did not have this pattern. In parallel, ADHD-I group had reduced degree centrality and clustering coefficient as well as increased closeness in task-positive and the default mode networks (prefrontal regions) after the training. More importantly, these reduced local functional processing mainly in the SVN were associated with less inattentive/internalizing problems after 8-week BCI-based intervention across ADHD patients. Our findings suggest that the BCI-based attention training facilitates behavioral improvement in ADHD children by reorganizing brain functional network from more regular to more random configurations, particularly renormalizing salience network processing. Future long-term longitudinal neuroimaging studies are needed to develop the BCI-based intervention approach to promote brain maturation in ADHD.

F156. LONGITUDINAL WORKING MEMORY FUNCTIONAL DYSCONNECTIVITY REFLECTS HETEROGENEITY IN INDIVIDUALS AT ULTRA HIGH RISK FOR PSYCHOSIS

Abstract Background Variation in trajectories of Ultra high-risk (UHR) psychosis mental state posts challenge to schizophrenia prevention or onset delay intervention. Our previous work described the heterogeneity at this prodromal stage of schizophrenia in both brain structure changes and resting-state functional network differences. Functional dysconnectivity can be one of the altered brain substrates underlying clinical symptoms. Lower resting-state functional connectivity (FC) within the salience network (SN) in schizophrenia was detectable at the UHR stage. FC between the frontoparietal network (FPN) and the SN was disrupted when network integration fell apart in the UHR state. FPN and SN are important for working memory (WM), which is largely compromised in schizophrenia and lesser in UHR group. Our previous work showed that WM task-related activation in the FPN and SN differed between the UHR and controls. Importantly, such differences varied with WM demands. Evidence has demonstrated that compared to resting-state FC, task-based FC may better predict behavioral performance. However, the WM-related FC in UHR group and its longitudinal changes are still largely unknown. To cover the gap, we sought to examine the heterogeneity in the WM task-related FC changes in a group of UHR participants over time. We expected WM-related FC would link to individual differences in clinical trajectories. Methods Based on the longitudinal changes of UHR state within 2 years, participants were divided into 3 groups: 42 controls, 34 UHR remitters (UHR-R) and 42 UHR non-remitters (UHR-NR). We acquired fMRI (TR/TE = 2000/30 ms, 3 x 3 x 4 mm3, 28 slices) when participants performed WM task at different WM demands, varying from information maintenance alone (low) to requiring both maintenance and manipulation (high). We used seed-based approach (gPPI) to compare task-related FC of the FPN and the SN among groups. Voxel-wise FC with six seeds (bilateral anterior insula, parietal, and dorsal lateral prefrontal cortex, identified based on task activation) was regressed on WM demands and groups, controlling for age, gender, education, ethnicity, handedness and task accuracy. Linear mixed modeling methods were used to test longitudinal FC changes and the association between FC and clinical syndromes. Results Task performance was worse at high WM demand as expected, but no significant difference was found between groups or over time. Compared to controls, higher FC between the FPN (superior parietal gyrus) and the SN (insula) at low demand was observed in the UHR-NR group at baseline. Within the SN, WM-demand related FC between right insula and thalamus varied among 3 groups: low FC at low demand and high FC at high demand in controls; high FC at low demand but low FC at high demand in the UHR-R group. In contrast, UHR-NR group had high thalamus-insula FC in both WM demands. Moreover, longitudinal FC increase only occurred within the SN at high WM demand in the UHR-R group, while other task-related baseline group differences of FC remained stable over time. Importantly, the rate of intra-SN increase of FC over time at higher WM demand was associated with decline of the positive psychosis syndromes in the UHR-R group. Discussion In support of the functional dysconnectivity hypothesis, our study indicated that UHR state was accompanied by altered brain FC during WM task performance. In contrast to lower SN FC at rest, UHR state showed SN hyper-connectivity in task with low WM demand, suggesting the importance of studying UHR both at resting and in task. Importantly, intra-SN FC increase at high WM demand was linked to positive psychosis syndrome reduction in remitters, while no FC changes if UHR state persisted. We argued that task FC could reflect the clinical heterogeneity of the UHR group.

Brain-computer interface and its applications in cognitive training

We investigated the use of Brain-Computer Interface (BCI) in cognitive training. We developed a BCI to quantify a persons attention level. Based on this algorithm, a feedforward mechanism is then used to build gaming interfaces for cognitive training. Several clinical trials have been conducted and significant improvement has been achieved in both children with ADHD and elderly with cognitive decline. Pivotal trials to demonstrate the efficacy of cognitive training are under way in both children and elderly subjects.