Dr Nikitas Koussis

Alzheimer's disease (AD) brain markers are needed to select people with early-stage AD for clinical trials and as quantitative endpoint measures in trials. Using 10 clinical cohorts (N = 9140) and the community volunteer UK Biobank (N = 37,664) we performed region of interest (ROI) and vertex-wise analyses of grey-matter structure (thickness, surface area and volume). We identified 94 trait-ROI significant associations, and 307 distinct cluster of vertex-associations, which partly overlap the ROI associations. For AD versus controls, smaller hippocampus, amygdala and of the medial temporal lobe (fusiform and parahippocampal gyri) was confirmed and the vertex-wise results provided unprecedented localisation of some of the associated region. We replicated AD associated differences in several subcortical (putamen, accumbens) and cortical regions (inferior parietal, postcentral, middle temporal, transverse temporal, inferior temporal, paracentral, superior frontal). These grey-matter regions and their relative effect sizes can help refine our understanding of the brain regions that may drive or precede the widespread brain atrophy observed in AD. An AD grey-matter score evaluated in independent cohorts was significantly associated with cognition, MCI status, AD conversion (progression from cognitively normal or MCI to AD), genetic risk, and tau concentration in individuals with none or mild cognitive impairments (AUC in 0.54¿0.70, p-value < 5e-4). In addition, some of the grey-matter regions associated with cognitive impairment, progression to AD ('conversion'), and cognition/functional scores were also associated with AD, which sheds light on the grey-matter markers of disease stages, and their relationship with cognitive or functional impairment. Our multi-cohort approach provides robust and fine-grained maps the grey-matter structures associated with AD, symptoms, and progression, and calls for even larger initiatives to unveil the full complexity of grey-matter structure in AD.

Background and Hypothesis: Impairments in the expression, experience, and recognition of emotion are common in early psychosis (EP). Computational accounts of psychosis suggest disrupted top-down modulation by the cognitive control system (CCS) on perceptual circuits underlies psychotic experiences, but their role in emotional deficits in EP is unknown. Study Design: The affective go/no-go task was used to probe inhibitory control during the presentation of calm or fearful faces in young persons with EP and matched controls. Computational modeling of functional magnetic resonance imaging (fMRI) data were performed using dynamic causal modeling (DCM). The influence of the CCS on perceptual and emotional systems was examined using parametric empirical bayes. Study Results: When inhibiting motor response to fearful faces, EP participants showed higher brain activity in the right posterior insula (PI). To explain this, we used DCM to model effective connectivity between the PI, regions from the CCS activated during inhibition (dorsolateral prefrontal cortex [DLPFC] and anterior insula [AI]), and a visual input region, the lateral occipital cortex (LOC). EP participants exerted a stronger top-down inhibition from the DLPFC to the LOC than controls. Within the EP cohort, increased top-down connectivity between the LOC and AI was associated with a higher burden of negative symptoms. Conclusions: Young persons with a recent onset of psychosis show a disturbance in the cognitive control of emotionally salient stimuli and the suppression of irrelevant distractors. These changes are associated with negative symptoms, suggesting new targets for the remediation of emotional deficits in young persons with EP.

Executive dysfunctions in early psychosis (EP) are subtle but persistent, hindering recovery. We asked whether changes in the cognitive control system (CCS) disrupt the response to increased cognitive load in persons with EP. In all, 30 EP and 30 control participants undertook multimodal MRI. Computational models of structural and effective connectivity amongst regions in the CCS were informed by cortical responses to the multi-source interference task, a paradigm that selectively introduces stimulus conflict. EP participants showed greater activation of CCS regions, including the superior parietal cortex, and were disproportionately slower at resolving stimulus conflict in the task. Computational models of the effective connectivity underlying this behavioral response suggest that the normative (control) group resolved stimulus conflict through an efficient and direct modulation of gain between the visual cortex and the anterior insula (AI). In contrast, the EP group utilized an indirect path, with parallel and multi-region hops to resolve stimulus conflict at the AI. Individual differences in task performance were dependent on initial linear gain modulations in the EP group versus a single nonlinear modulation in the control group. Effective connectivity in the EP group was associated with reduced structural integration amongst those connections critical for task execution. CCS engagement during stimulus conflict is hampered in EP owing to inefficient use of higher-order network interactions, with high tonic gain impeding task-relevant (phasic) signal amplification.

The temporal pole (TP) is an associative cortical region required for complex cognitive functions such as social and emotional cognition. However, mapping the TP with functional magnetic resonance imaging is technically challenging and thus understanding its interaction with other key emotional circuitry, such as the amygdala, remains elusive. We exploited the unique advantages of stereo-electroencephalography (sEEG) to assess the responses of the TP and the amygdala during the perception of emotionally salient stimuli of pictures, music and movies. These stimuli consistently elicited high gamma responses (70¿140 Hz) in both the TP and the amygdala, accompanied by functional connectivity in the low frequency range (2¿12 Hz). Computational analyses suggested that the TP drove this effect in the theta frequency range, modulated by the emotional valence of the stimuli. Notably, cross-frequency analysis indicated the phase of theta oscillations in the TP modulated the amplitude of high gamma activity in the amygdala. These results were reproducible across three types of sensory inputs including naturalistic stimuli. Our results suggest that multimodal emotional stimuli induce a hierarchical influence of the TP over the amygdala.