Scott Sponheim

BackgroundSchizophrenia is associated with hypoactivation of reward sensitive brain areas during reward anticipation. However, it is unclear whether these neural functions are similarly impaired in other disorders with psychotic symptomatology or individuals with genetic liability for psychosis. If abnormalities in reward sensitive brain areas are shared across individuals with psychotic psychopathology and people with heightened genetic liability for psychosis, there may be a common neural basis for symptoms of diminished pleasure and motivation.MethodsWe compared performance and neural activity in 123 people with a history of psychosis (PwP), 81 of their first-degree biological relatives, and 49 controls during a modified Monetary Incentive Delay task during fMRI.ResultsPwP exhibited hypoactivation of the striatum and anterior insula (AI) during cueing of potential future rewards with each diagnostic group …

BackgroundNeural oscillations support perception, attention, and higher-order decision making. Aberrations in the strength or consistency of these oscillations in response to stimuli may underlie impaired visual perception and attention in schizophrenia. Here, we examined the phase and power of alpha oscillations (8–12 Hz) as well as aspects of beta and theta frequency oscillations during a demanding visual sustained attention task.MethodsPatients with schizophrenia (n = 74) and healthy control participants (n = 68) completed the degraded stimulus continuous performance task during electroencephalography. We used time-frequency analysis to evaluate the consistency (intertrial phase coherence) of the alpha cycle shortly after stimulus presentation (50–250 ms). For oscillation strength, we examined event-related desynchronization in a later window associated with decision making (360–700 ms).Results …

The chronic mental health consequences of mild traumatic brain injury (TBI) are a leading cause of disability. This is surprising given the expectation of significant recovery after mild TBI, which suggests that other injury-related factors may contribute to long-term adverse outcomes. The objective of this study was to determine how number of prior injuries, gender, and environment/context of injury may contribute to depressive symptoms after mild TBI among deployed United States service members and veterans (SMVs). Data from the Long-term Impact of Military-Relevant Brain Injury Consortium Prospective Longitudinal Study was used to assess TBI injury characteristics and depression scores previously measured on the Patient Health Questionnaire-9 (PHQ-9) among a sample of 1456 deployed SMVs. Clinical diagnosis of mild TBI was defined via a multi-step process centered on a structured face-to-face …

Background and Hypothesis Cognitive control deficits are prominent in individuals with psychotic psychopathology. Studies providing evidence for deficits in proactive control generally examine average performance and not variation across trials for individuals—potentially obscuring detection of essential contributors to cognitive control. Here, we leverage intertrial variability through drift-diffusion models (DDMs) aiming to identify key contributors to cognitive control deficits in psychosis. Study Design People with psychosis (PwP; N = 122), their first-degree biological relatives (N = 78), and controls (N = 50) each completed 120 trials of the dot pattern expectancy (DPX) cognitive control task. We fit full hierarchical DDMs to response and reaction time (RT) data for individual trials and then used classification models to compare the DDM parameters with conventional …

BackgroundThalamic and cortical structural differences have been reported in individuals with schizophrenia (SCZ) though studies on familial risk for schizophrenia (FHR) show mixed results. Most studies have often examined the thalamus as a whole, and as a single region-of-interest. We, therefore, investigated whether local and global thalamic-related structural alterations (respectively, volume of thalamic subdivisions and thalamo-cortical/cortico-cortical structural co-variation) vary as a function of risk for schizophrenia.MethodsHigh-resolution T1-weighted images from 28 cross-sectional samples (4635 participants: 1356 SCZ, 195 FHR, 3084 controls (HC)) were analyzed through the ENIGMA Consortium. Random-effects meta-analysis and network analysis (pFDR< 0.05) were conducted on (i) local thalamic structural alterations (ie, anterior, intralaminar, medial, posterior, pulvinar, ventral-posterior, and ventral …

Although the cerebellum contributes to higher-order cognitive and emotional functions relevant to posttraumatic stress disorder (PTSD), prior research on cerebellar volume in PTSD is scant, particularly when considering subregions that differentially map on to motor, cognitive, and affective functions. In a sample of 4215 adults (PTSD n = 1642; Control n = 2573) across 40 sites from the ENIGMA-PGC PTSD working group, we employed a new state-of-the-art deep-learning based approach for automatic cerebellar parcellation to obtain volumetric estimates for the total cerebellum and 28 subregions. Linear mixed effects models controlling for age, gender, intracranial volume, and site were used to compare cerebellum volumes in PTSD compared to healthy controls (88% trauma-exposed). PTSD was associated with significant grey and white matter reductions of the cerebellum. Compared to controls, people with …

Schizophrenia is a prototypical network disorder with widespread brain-morphological alterations, yet it remains unclear whether these distributed alterations robustly reflect the underlying network layout. We tested whether large-scale structural alterations in schizophrenia relate to normative structural and functional connectome architecture, and systematically evaluated robustness and generalizability of these network-level alterations. Leveraging anatomical MRI scans from 2439 adults with schizophrenia and 2867 healthy controls from 26 ENIGMA sites and normative data from the Human Connectome Project (n = 207), we evaluated structural alterations of schizophrenia against two network susceptibility models: (i) hub vulnerability, which examines associations between regional network centrality and magnitude of disease-related alterations; (ii) epicenter mapping, which identifies regions whose typical …

Formal thought disorder (FTD) is a clinical key factor in schizophrenia, but the neurobiological underpinnings remain unclear. In particular, the relationship between FTD symptom dimensions and patterns of regional brain volume loss in schizophrenia remains to be established in large cohorts. Even less is known about the cellular basis of FTD. Our study addresses these major obstacles by enrolling a large multi-site cohort acquired by the ENIGMA Schizophrenia Working Group (752 schizophrenia patients and 1256 controls), to unravel the neuroanatomy of FTD in schizophrenia and using virtual histology tools on implicated brain regions to investigate the cellular basis. Based on the findings of previous clinical and neuroimaging studies, we decided to separately explore positive, negative and total formal thought disorder. We used virtual histology tools to relate brain structural changes associated with FTD to …

Altered brain chemistry is thought to contribute to impairments in cognitive and perceptual functioning in people with psychotic psychopathology (PwPP). As heritable genetic factors shape the development of psychosis, these alterations in brain chemistry may extend to biological relatives of PwPP. Magnetic resonance spectroscopy (MRS) is a non-invasive method for quantifying the concentration of various neurochemicals in the human brain. A number of MRS studies in different brain regions have been performed in PwPP, and to a lesser extent in relatives, but results have been largely mixed. There are a number of methodological issues that may have influenced previous findings. We show here that when such issues are addressed, MRS reveals a pattern of neurometabolic dysfunction in PwPP. We acquired MRS data at 7 tesla with an ultra-short echo time (TE = 8 ms) sequence in both occipital and prefrontal cortices from 43 healthy controls, 42 first-degree biological relatives, and 64 PwPP. We saw reduced levels of N-acetyl-aspartate (NAA) in the occipital lobe in PwPP and their relatives (versus controls), and lower N-acetyl-aspartyl-glutamate (NAAG) in prefrontal cortex in PwPP versus controls. Surprisingly, we also saw markedly increased levels of glucose in both occipital and prefrontal cortices in PwPP. Hierarchical clustering analyses showed that higher glucose levels were linked to higher psychiatric symptom levels and impairments in visual task performance. Together, our findings point to a disruption in neural metabolism across multiple brain areas in PwPP that is associated with impaired cognitive and perceptual functioning.

Posttraumatic stress disorder (PTSD) is associated with lower cortical thickness (CT) in prefrontal, cingulate, and insular cortices in diverse trauma-affected samples. However, some studies have failed to detect differences between PTSD patients and healthy controls or reported that PTSD is associated with greater CT. Using data-driven dimensionality reduction, we sought to conduct a well-powered study to identify vulnerable networks without regard to neuroanatomic boundaries. Moreover, this approach enabled us to avoid the excessive burden of multiple comparison correction that plagues vertex-wise methods. We derived structural covariance networks (SCNs) by applying non-negative matrix factorization (NMF) to CT data from 961 PTSD patients and 1124 trauma-exposed controls without PTSD. We used regression analyses to investigate associations between CT within SCNs and PTSD diagnosis (with …

Post-traumatic stress disorder (PTSD) genetics are characterized by lower discoverability than most other psychiatric disorders. The contribution to biological understanding from previous genetic studies has thus been limited. We performed a multi-ancestry meta-analysis of genome-wide association studies across 1,222,882 individuals of European ancestry (137,136 cases) and 58,051 admixed individuals with African and Native American ancestry (13,624 cases). We identified 95 genome-wide significant loci (80 new). Convergent multi-omic approaches identified 43 potential causal genes, broadly classified as neurotransmitter and ion channel synaptic modulators (for example, GRIA1, GRM8 and CACNA1E), developmental, axon guidance and transcription factors (for example, FOXP2, EFNA5 and DCC), synaptic structure and function genes (for example, PCLO, NCAM1 and PDE4B) and endocrine or immune …

BackgroundIntrusive traumatic re-experiencing domain (ITRED) was recently introduced as a novel perspective on posttraumatic psychopathology, proposing to focus research of posttraumatic stress disorder (PTSD) on the unique symptoms of intrusive and involuntary re-experiencing of the trauma, namely, intrusive memories, nightmares, and flashbacks. The aim of the present study was to explore ITRED from a neural network connectivity perspective.MethodsData were collected from 9 sites taking part in the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) PTSD Consortium (n = 584) and included itemized PTSD symptom scores and resting-state functional connectivity (rsFC) data. We assessed the utility of rsFC in classifying PTSD, ITRED-only (no PTSD diagnosis), and trauma-exposed (TE)–only (no PTSD or ITRED) groups using a machine learning approach, examining well-known …

ImportanceMany psychiatric outcomes share a common etiologic pathway reflecting behavioral disinhibition, generally referred to as externalizing (EXT) disorders. Recent genome-wide association studies (GWASs) have demonstrated the overlap between EXT disorders and important aspects of veterans’ health, such as suicide-related behaviors and substance use disorders (SUDs).ObjectiveTo explore correlates of risk for EXT disorders within the Veterans Health Administration (VA) Million Veteran Program (MVP).Design, Setting, and ParticipantsA series of phenome-wide association studies (PheWASs) of polygenic risk scores (PGSs) for EXT disorders was conducted using electronic health records. First, ancestry-specific PheWASs of EXT PGSs were conducted in the African, European, and Hispanic or Latin American ancestries. Next, a conditional PheWAS, covarying for PGSs of comorbid psychiatric …

Blast-related mild traumatic brain injury (BR mTBI) is a critical research area in recent combat veterans due to increased prevalence of survived blasts. Post-BR mTBI outcomes are highly heterogeneous and defining neurological differences may help in discrimination and prediction of cognitive outcomes. This study investigates whether white matter integrity, measured with diffusion tensor imaging (DTI), could influence how remote BR mTBI history is associated with executive control. The sample included 151 Veterans from the Minneapolis Veterans Affairs Medical Center who were administered a clinical/TBI assessment, neuropsychological battery, and DTI scan as part of a larger battery. From previous research, six white matter tracts were identified as having a putative relationship with blast severity: the cingulum, hippocampal cingulum, corticospinal tract, inferior fronto-occipital fasciculus, superior longitudinal …

Mental health conditions and traumatic brain injury (TBI) are common among Veterans and often negatively impact Veterans, their families, and their communities. The Department of Veterans Affairs (VA) devotes considerable resources to treating these conditions and improving diagnosis and treatment outcomes is an ongoing VA priority.

Perceptual surround suppression is a phenomenon in which the perceived contrast of a stimulus is reduced when accompanied by a surrounding stimulus. This effect is influenced by various stimulus features of the center-surround, including relative orientation (ie, orientation-dependent surround suppression [ODSS]). Patients with schizophrenia (SZ) often exhibit reduced ODSS, though the neurophysiological correlates of this atypical perception are not yet fully understood. Accordingly, the present study examined differences in electrophysiological (EEG) response between SZ (N= 28), healthy controls (HC; N= 26), patients with bipolar disorder (BP; N= 29) and first-degree relatives of both patient groups (SZR, BPR; N= 25, N= 19) to probe whether atypical neural functions during ODSS are related to severe mental illness more broadly, and/or mark genetic liability for psychosis. Participants indicated whether a …

Adolescent onset is common in bipolar disorders (BDs) and is associated with a worse illness course in adulthood. A model of BDs suggests that a dysregulated behavioral approach system (BAS), a neural system that mobilizes reward-seeking behavior, is at the root of BDs. Normative adolescence is often accompanied by dynamic changes to neural structures underlying the BAS and related cognitive processes. It is possible that adolescent-onset BDs is associated with abnormal BAS neurodevelopment. Consistently, the present study is the first to compare specific BAS-relevant anticipatory and consummatory reward processes as indexed by event-related potentials (ERPs) in adolescents with BDs and typically developing peers. Using a sample of 43 adolescents with BDs and 56 without psychopathology, we analyzed N1 and P3 responses to anticipatory cues and feedback-related negativity (FRN) and P3 …

Posttraumatic stress disorder (PTSD) genetics are characterized by lower discoverability than most other psychiatric disorders. The contribution to biological understanding from previous genetic studies has thus been limited. We performed a multi-ancestry meta-analysis of genome-wide association studies across 1,222,882 individuals of European ancestry (137,136 cases) and 58,051 admixed individuals with African and Native American ancestry (13,624 cases). We identified 95 genome-wide significant loci (80 novel). Convergent multi-omic approaches identified 43 potential causal genes, broadly classified as neurotransmitter and ion channel synaptic modulators (e.g., GRIA1, GRM8, CACNA1E), developmental, axon guidance, and transcription factors (e.g., FOXP2, EFNA5, DCC), synaptic structure and function genes (e.g., PCLO, NCAM1, PDE4B), and endocrine or immune regulators (e.g., ESR1, TRAF3, TANK). Additional top genes influence stress, immune, fear, and threat-related processes, previously hypothesized to underlie PTSD neurobiology. These findings strengthen our understanding of neurobiological systems relevant to PTSD pathophysiology, while also opening new areas for investigation.

Introduction Among patients with traumatic brain injury (TBI), postural instability often persists chronically with negative consequences such as higher fall risk. One explanation may be reduced executive function (EF) required to effectively process, interpret and combine, sensory information. In other populations, a decline in higher cognitive functions are associated with a decline in walking and balance skills. Considering the link between EF decline and reduction in functional capacity, we investigated whether specific tests of executive function could predict balance function in a cohort of individuals with a history of chronic mild TBI (mTBI) and compared to individuals with a negative history of mTBI. Methods Secondary analysis was performed on the local LIMBIC-CENC cohort (N = 338, 259 mTBI, mean 45 ± STD 10 age). Static balance was assessed with the sensory organization test (SOT). Hierarchical regression was used for each EF test outcome using the following blocks: (1) the number of TBIs sustained, age, and sex; (2) the separate Trail making test (TMT); (3) anti-saccade eye tracking items (error, latency, and accuracy); (4) Oddball distractor stimulus P300 and N200 at PZ and FZ response; and (5) Oddball target stimulus P300 and N200 at PZ and FZ response. Results The full model with all predictors accounted for between 15.2% and 21.5% of the variability in the balance measures. The number of TBI's) showed a negative association with the SOT2 score (p = 0.002). Additionally, longer times to complete TMT part B were shown to be related to a worse SOT1 score (p = 0.038). EEG distractors had the most influence on the SOT3 …

Attentional filtering has long been suggested to be a core deficit of schizophrenia. Recent work has emphasized the important distinction between attentional control, which involves the voluntary selection of a particular stimulus for focused processing, and implementation of selection, which involves the mechanisms that actually enhance the stimulus selected via filtering processes. We recorded electroencephalography data from people with schizophrenia (PSZ), their first-degree relatives (REL) and healthy controls (CTRL) during performance of a resistance to attentional capture task that tapped attentional control and implementation of selection measured during a brief period of attentional maintenance. Event-related potentials (ERPs) during attentional control and maintenance of attention revealed diminished neural responding in PSZ. ERPs during attentional control predicted performance on the visual …