Acute TMS/fMRI response explains offline TMS network effects - An interleaved TMS-fMRI study.

BACKGROUND: Transcranial magnetic stimulation (TMS) is an FDA-approved therapeutic option for treatment resistant depression. However, exact mechanisms-of-action are not fully understood and individual responses are variable. Moreover, although previously suggested, the exact network effects underlying TMS' efficacy are poorly understood as of today. Although, it is supposed that DLPFC stimulation indirectly modulates the sgACC, recent evidence is sparse. METHODS: Here, we used concurrent interleaved TMS/fMRI and state-of-the-science purpose-designed MRI head coils to delineate networks and downstream regions activated by DLPFC-TMS. RESULTS: We show that regions of increased acute BOLD signal activation during TMS resemble a resting-state brain network previously shown to be modulated by offline TMS. There was a topographical overlap in wide spread cortical and sub-cortical areas within this specific RSN#17 derived from the 1000 functional connectomes project. CONCLUSION: These data imply a causal relation between DLPFC-TMS and activation of the ACC and a broader network that has been implicated in MDD. In the broader context of our recent work, these data imply a direct relation between initial changes in BOLD activity mediated by connectivity to the DLPFC target site, and later consolidation of connectivity between these regions. These insights advance our understanding of the mechanistic targets of DLPFC-TMS and may provide novel opportunities to characterize and optimize TMS therapy in other neurological and psychiatric disorders.

Structure-function coupling in the human connectome: A machine learning approach.

While the function of most biological systems is tightly constrained by their structure, current evidence suggests that coupling between the structure and function of brain networks is relatively modest. We aimed to investigate whether the modest coupling between connectome structure and function is a fundamental property of nervous systems or a limitation of current brain network models. We developed a new deep learning framework to predict an individual's brain function from their structural connectome, achieving prediction accuracies that substantially exceeded state-of-the-art biophysical models (group: R=0.9±0.1, individual: R=0.55±0.1). Crucially, brain function predicted from an individual's structural connectome explained significant inter-individual variation in cognitive performance. Our results suggest that structure-function coupling in human brain networks is substantially tighter than previously suggested. We establish the margin by which current brain network models can be improved and demonstrate how deep learning can facilitate investigation of relations between brain function and behavior.

Widespread white matter microstructural differences in schizophrenia across 4322 individuals: results from the ENIGMA Schizophrenia DTI Working Group.

The regional distribution of white matter (WM) abnormalities in schizophrenia remains poorly understood, and reported disease effects on the brain vary widely between studies. In an effort to identify commonalities across studies, we perform what we believe is the first ever large-scale coordinated study of WM microstructural differences in schizophrenia. Our analysis consisted of 2359 healthy controls and 1963 schizophrenia patients from 29 independent international studies; we harmonized the processing and statistical analyses of diffusion tensor imaging (DTI) data across sites and meta-analyzed effects across studies. Significant reductions in fractional anisotropy (FA) in schizophrenia patients were widespread, and detected in 20 of 25 regions of interest within a WM skeleton representing all major WM fasciculi. Effect sizes varied by region, peaking at (d=0.42) for the entire WM skeleton, driven more by peripheral areas as opposed to the core WM where regions of interest were defined. The anterior corona radiata (d=0.40) and corpus callosum (d=0.39), specifically its body (d=0.39) and genu (d=0.37), showed greatest effects. Significant decreases, to lesser degrees, were observed in almost all regions analyzed. Larger effect sizes were observed for FA than diffusivity measures; significantly higher mean and radial diffusivity was observed for schizophrenia patients compared with controls. No significant effects of age at onset of schizophrenia or medication dosage were detected. As the largest coordinated analysis of WM differences in a psychiatric disorder to date, the present study provides a robust profile of widespread WM abnormalities in schizophrenia patients worldwide. Interactive three-dimensional visualization of the results is available at www.enigma-viewer.org.

Neuregulin-1 (NRG1) polymorphisms linked with psychosis transition are associated with enlarged lateral ventricles and white matter disruption in schizophrenia.

BACKGROUND: Two single-nucleotide polymorphisms (SNPs) (rs4281084 and rs12155594) within the neuregulin-1 (NRG1) gene have been associated with psychosis transition. However, the neurobiological changes associated with these SNPs remain unclear. We aimed to determine what relationship these two SNPs have on lateral ventricular volume and white matter integrity, as abnormalities in these brain structures are some of the most consistent in schizophrenia. METHODS: Structural (n = 370) and diffusion (n = 465) magnetic resonance imaging data were obtained from affected and unaffected individuals predominantly of European descent. The SNPs rs4281084, rs12155594, and their combined allelic load were examined for their effects on lateral ventricular volume, fractional anisotropy (FA) as well as axial (AD) and radial (RD) diffusivity. Additional exploratory analyses assessed NRG1 effects on gray matter volume, cortical thickness, and surface area throughout the brain. RESULTS: Individuals with a schizophrenia age of onset ⩽25 and a combined allelic load ⩾3 NRG1 risk alleles had significantly larger right (up to 50%, p adj = 0.01) and left (up to 45%, p adj = 0.05) lateral ventricle volumes compared with those with allelic loads of less than three. Furthermore, carriers of three or more risk alleles, regardless of age of onset and case status, had significantly reduced FA and elevated RD but stable AD in the frontal cortex compared with those carrying fewer than three risk alleles. CONCLUSIONS: Our findings build on a growing body of research supporting the functional importance of genetic variation within the NRG1 gene and complement previous findings implicating the rs4281084 and rs12155594 SNPs as markers for psychosis transition.

White matter connectivity disruptions in early and chronic schizophrenia.

BACKGROUND: White matter disruptions in schizophrenia have been widely reported, but it remains unclear whether these abnormalities differ between illness stages. We mapped the connectome in patients with recently diagnosed and chronic schizophrenia and investigated the extent and overlap of white matter connectivity disruptions between these illness stages. METHODS: Diffusion-weighted magnetic resonance images were acquired in recent-onset (n = 19) and chronic patients (n = 45) with schizophrenia, as well as age-matched controls (n = 87). Whole-brain fiber tracking was performed to quantify the strength of white matter connections. Connections were tested for significant streamline count reductions in recent-onset and chronic groups, relative to separate age-matched controls. Permutation tests were used to assess whether disrupted connections significantly overlapped between chronic and recent-onset patients. Linear regression was performed to test whether connectivity was strongest in controls, weakest in chronic patients, and midway between these extremities in recent-onset patients (controls > recent-onset > chronic). RESULTS: Compared with controls, chronic patients displayed a widespread network of connectivity disruptions (p < 0.01). In contrast, connectivity reductions were circumscribed to the anterior fibers of the corpus callosum in recent-onset patients (p < 0.01). A significant proportion of disrupted connections in recent-onset patients (86%) coincided with disrupted connections in chronic patients (p < 0.01). Linear regression revealed that chronic patients displayed reduced connectivity relative to controls, while recent-onset patients showed an intermediate reduction compared with chronic patients (p < 0.01). CONCLUSIONS: Connectome pathology in recent-onset patients with schizophrenia is confined to select tracts within a more extensive network of white matter connectivity disruptions found in chronic illness. These findings may suggest a trajectory of progressive deterioration of connectivity in schizophrenia.

Brain network disintegration as a final common pathway for delirium: a systematic review and qualitative meta-analysis.

Delirium is an acute neuropsychiatric syndrome characterized by altered levels of attention and awareness with cognitive deficits. It is most prevalent in elderly hospitalized patients and related to poor outcomes. Predisposing risk factors, such as older age, determine the baseline vulnerability for delirium, while precipitating factors, such as use of sedatives, trigger the syndrome. Risk factors are heterogeneous and the underlying biological mechanisms leading to vulnerability for delirium are poorly understood. We tested the hypothesis that delirium and its risk factors are associated with consistent brain network changes. We performed a systematic review and qualitative meta-analysis and included 126 brain network publications on delirium and its risk factors. Findings were evaluated after an assessment of methodological quality, providing N=99 studies of good or excellent quality on predisposing risk factors, N=10 on precipitation risk factors and N=7 on delirium. Delirium was consistently associated with functional network disruptions, including lower EEG connectivity strength and decreased fMRI network integration. Risk factors for delirium were associated with lower structural connectivity strength and less efficient structural network organization. Decreased connectivity strength and efficiency appear to characterize structural brain networks of patients at risk for delirium, possibly impairing the functional network, while functional network disintegration seems to be a final common pathway for the syndrome.

PET imaging of putative microglial activation in individuals at ultra-high risk for psychosis, recently diagnosed and chronically ill with schizophrenia.

We examined putative microglial activation as a function of illness course in schizophrenia. Microglial activity was quantified using [11C](R)-(1-[2-chrorophynyl]-N-methyl-N-[1-methylpropyl]-3 isoquinoline carboxamide (11C-(R)-PK11195) positron emission tomography (PET) in: (i) 10 individuals at ultra-high risk (UHR) of psychosis; (ii) 18 patients recently diagnosed with schizophrenia; (iii) 15 patients chronically ill with schizophrenia; and, (iv) 27 age-matched healthy controls. Regional-binding potential (BPND) was calculated using the simplified reference-tissue model with four alternative reference inputs. The UHR, recent-onset and chronic patient groups were compared to age-matched healthy control groups to examine between-group BPND differences in 6 regions: dorsal frontal, orbital frontal, anterior cingulate, medial temporal, thalamus and insula. Correlation analysis tested for BPND associations with gray matter volume, peripheral cytokines and clinical variables. The null hypothesis of equality in BPND between patients (UHR, recent-onset and chronic) and respective healthy control groups (younger and older) was not rejected for any group comparison or region. Across all subjects, BPND was positively correlated to age in the thalamus (r=0.43, P=0.008, false discovery rate). No correlations with regional gray matter, peripheral cytokine levels or clinical symptoms were detected. We therefore found no evidence of microglial activation in groups of individuals at high risk, recently diagnosed or chronically ill with schizophrenia. While the possibility of 11C-(R)-PK11195-binding differences in certain patient subgroups remains, the patient cohorts in our study, who also displayed normal peripheral cytokine profiles, do not substantiate the assumption of microglial activation in schizophrenia as a regular and defining feature, as measured by 11C-(R)-PK11195 BPND.

Hippocampal harms, protection and recovery following regular cannabis use.

Shifting policies towards legalisation of cannabis for therapeutic and recreational use raise significant ethical issues for health-care providers seeking evidence-based recommendations. We investigated whether heavy cannabis use is associated with persistent harms to the hippocampus, if exposure to cannabidiol offers protection, and whether recovery occurs with abstinence. To do this, we assessed 111 participants: 74 long-term regular cannabis users (with an average of 15.4 years of use) and 37 non-user healthy controls. Cannabis users included subgroups of participants who were either exposed to Δ9-tetrahydrocannabinol (THC) but not to cannabidiol (CBD) or exposed to both, and former users with sustained abstinence. Participants underwent magnetic resonance imaging from which three measures of hippocampal integrity were assessed: (i) volume; (ii) fractional anisotropy; and (iii) N-acetylaspartate (NAA). Three curve-fitting models across the entire sample were tested for each measure to examine whether cannabis-related hippocampal harms are persistent, can be minimised (protected) by exposure to CBD or recovered through long-term abstinence. These analyses supported a protection and recovery model for hippocampal volume (P=0.003) and NAA (P=0.001). Further pairwise analyses showed that cannabis users had smaller hippocampal volumes relative to controls. Users not exposed to CBD had 11% reduced volumes and 15% lower NAA concentrations. Users exposed to CBD and former users did not differ from controls on any measure. Ongoing cannabis use is associated with harms to brain health, underpinned by chronic exposure to THC. However, such harms are minimised by CBD, and can be recovered with extended periods of abstinence.