Network Connectivity Alterations across the MAPT Mutation Clinical Spectrum.

OBJECTIVE: Microtubule-associated protein tau (MAPT) mutations cause frontotemporal lobar degeneration, and novel biomarkers are urgently needed for early disease detection. We used task-free functional magnetic resonance imaging (fMRI) mapping, a promising biomarker, to analyze network connectivity in symptomatic and presymptomatic MAPT mutation carriers. METHODS: We compared cross-sectional fMRI data between 17 symptomatic and 39 presymptomatic carriers and 81 controls with (1) seed-based analyses to examine connectivity within networks associated with the 4 most common MAPT-associated clinical syndromes (ie, salience, corticobasal syndrome, progressive supranuclear palsy syndrome, and default mode networks) and (2) whole-brain connectivity analyses. We applied K-means clustering to explore connectivity heterogeneity in presymptomatic carriers at baseline. Neuropsychological measures, plasma neurofilament light chain, and gray matter volume were compared at baseline and longitudinally between the presymptomatic subgroups defined by their baseline whole-brain connectivity profiles. RESULTS: Symptomatic and presymptomatic carriers had connectivity disruptions within MAPT-syndromic networks. Compared to controls, presymptomatic carriers showed regions of connectivity alterations with age. Two presymptomatic subgroups were identified by clustering analysis, exhibiting predominantly either whole-brain hypoconnectivity or hyperconnectivity at baseline. At baseline, these two presymptomatic subgroups did not differ in neuropsychological measures, although the hypoconnectivity subgroup had greater plasma neurofilament light chain levels than controls. Longitudinally, both subgroups showed visual memory decline (vs controls), yet the subgroup with baseline hypoconnectivity also had worsening verbal memory and neuropsychiatric symptoms, and extensive bilateral mesial temporal gray matter decline. INTERPRETATION: Network connectivity alterations arise as early as the presymptomatic phase. Future studies will determine whether presymptomatic carriers' baseline connectivity profiles predict symptomatic conversion. ANN NEUROL 2023;94:632-646.

Brain volumetric deficits in MAPT mutation carriers: a multisite study.

OBJECTIVE: MAPT mutations typically cause behavioral variant frontotemporal dementia with or without parkinsonism. Previous studies have shown that symptomatic MAPT mutation carriers have frontotemporal atrophy, yet studies have shown mixed results as to whether presymptomatic carriers have low gray matter volumes. To elucidate whether presymptomatic carriers have lower structural brain volumes within regions atrophied during the symptomatic phase, we studied a large cohort of MAPT mutation carriers using a voxelwise approach. METHODS: We studied 22 symptomatic carriers (age 54.7 ± 9.1, 13 female) and 43 presymptomatic carriers (age 39.2 ± 10.4, 21 female). Symptomatic carriers' clinical syndromes included: behavioral variant frontotemporal dementia (18), an amnestic dementia syndrome (2), Parkinson's disease (1), and mild cognitive impairment (1). We performed voxel-based morphometry on T1 images and assessed brain volumetrics by clinical subgroup, age, and mutation subtype. RESULTS: Symptomatic carriers showed gray matter atrophy in bilateral frontotemporal cortex, insula, and striatum, and white matter atrophy in bilateral corpus callosum and uncinate fasciculus. Approximately 20% of presymptomatic carriers had low gray matter volumes in bilateral hippocampus, amygdala, and lateral temporal cortex. Within these regions, low gray matter volumes emerged in a subset of presymptomatic carriers as early as their thirties. Low white matter volumes arose infrequently among presymptomatic carriers. INTERPRETATION: A subset of presymptomatic MAPT mutation carriers showed low volumes in mesial temporal lobe, the region ubiquitously atrophied in all symptomatic carriers. With each decade of age, an increasing percentage of presymptomatic carriers showed low mesial temporal volume, suggestive of early neurodegeneration.

Thalamo-cortical network hyperconnectivity in preclinical progranulin mutation carriers.

Mutations in progranulin (GRN) cause heterogeneous clinical syndromes, including behavioral variant frontotemporal dementia (bvFTD), primary progressive aphasia (PPA), corticobasal syndrome (CBS) and Alzheimer-type dementia (AD-type dementia). Human studies have shown that presymptomatic GRN carriers feature reduced connectivity in the salience network, a system targeted in bvFTD. Mice with homozygous deletion of GRN, in contrast, show thalamo-cortical hypersynchrony due to aberrant pruning of inhibitory synapses onto thalamo-cortical projection neurons. No studies have systematically explored the intrinsic connectivity networks (ICNs) targeted by the four GRN-associated clinical syndromes, or have forged clear links between human and mouse model findings. We compared 17 preclinical GRN carriers (14 "presymptomatic" clinically normal and three "prodromal" with mild cognitive symptoms) to healthy controls to assess for differences in cognitive testing and gray matter volume. Using task-free fMRI, we assessed connectivity in the salience network, a non-fluent variant primary progressive aphasia network (nfvPPA), the perirolandic network (CBS), and the default mode network (AD-type dementia). GRN carriers and controls showed similar performance on cognitive testing. Although carriers showed little evidence of brain atrophy, markedly enhanced connectivity emerged in all four networks, and thalamo-cortical hyperconnectivity stood out as a unifying feature. Voxelwise assessment of whole brain degree centrality, an unbiased graph theoretical connectivity metric, confirmed thalamic hyperconnectivity. These results show that human GRN disease and the prevailing GRN mouse model share a thalamo-cortical network hypersynchrony phenotype. Longitudinal studies will determine whether this network physiology represents a compensatory response as carriers approach symptom onset, or an early and sustained preclinical manifestation of lifelong progranulin haploinsufficiency.

Attenuated Neural Processing of Risk in Young Adults at Risk for Stimulant Dependence.

OBJECTIVE: Approximately 10% of young adults report non-medical use of stimulants (cocaine, amphetamine, methylphenidate), which puts them at risk for the development of dependence. This fMRI study investigates whether subjects at early stages of stimulant use show altered decision making processing. METHODS: 158 occasional stimulants users (OSU) and 50 comparison subjects (CS) performed a "risky gains" decision making task during which they could select safe options (cash in 20 cents) or gamble them for double or nothing in two consecutive gambles (win or lose 40 or 80 cents, "risky decisions"). The primary analysis focused on risky versus safe decisions. Three secondary analyses were conducted: First, a robust regression examined the effect of lifetime exposure to stimulants and marijuana; second, subgroups of OSU with >1000 (n = 42), or <50 lifetime marijuana uses (n = 32), were compared to CS with <50 lifetime uses (n = 46) to examine potential marijuana effects; third, brain activation associated with behavioral adjustment following monetary losses was probed. RESULTS: There were no behavioral differences between groups. OSU showed attenuated activation across risky and safe decisions in prefrontal cortex, insula, and dorsal striatum, exhibited lower anterior cingulate cortex (ACC) and dorsal striatum activation for risky decisions and greater inferior frontal gyrus activation for safe decisions. Those OSU with relatively more stimulant use showed greater dorsal ACC and posterior insula attenuation. In comparison, greater lifetime marijuana use was associated with less neural differentiation between risky and safe decisions. OSU who chose more safe responses after losses exhibited similarities with CS relative to those preferring risky options. DISCUSSION: Individuals at risk for the development of stimulant use disorders presented less differentiated neural processing of risky and safe options. Specifically, OSU show attenuated brain response in regions critical for performance monitoring, reward processing and interoceptive awareness. Marijuana had additive effects by diminishing neural risk differentiation.

Common and disorder-specific neural responses to emotional faces in generalised anxiety, social anxiety and panic disorders.

BACKGROUND: Although evidence exists for abnormal brain function across various anxiety disorders, direct comparison of neural function across diagnoses is needed to elicit abnormalities common across disorders and those distinct to a particular diagnosis. AIMS: To delineate common and distinct abnormalities within generalised anxiety (GAD), panic and social anxiety disorder (SAD) during affective processing. METHOD: Fifty-nine adults (15 with GAD, 15 with panic disorder, 14 with SAD, and 15 healthy controls) underwent functional magnetic resonance imaging while completing a facial emotion matching task with fearful, angry and happy faces. RESULTS: Greater differential right amygdala activation to matching fearful v. happy facial expressions related to greater negative affectivity (i.e. trait anxiety) and was heightened across all anxiety disorder groups compared with controls. Collapsing across emotional face types, participants with panic disorder uniquely displayed greater posterior insula activation. CONCLUSIONS: These preliminary results highlight a common neural basis for clinical anxiety in these diagnoses and also suggest the presence of disorder-specific dysfunction.

Cognitive-behavioral therapy for generalized anxiety disorder is associated with attenuation of limbic activation to threat-related facial emotions.

BACKGROUND: The neural processes underlying the benefits of cognitive behavioral treatment (CBT) for generalized anxiety disorder (GAD) are not well understood. METHODS: Twenty-one (n=21) adults with a principal diagnosis of GAD and eleven (n=11) non-anxious healthy controls (HC) underwent functional magnetic resonance imaging while completing a facial emotion processing task. Responses to threat-related emotionality (i.e., the contrast of fear and angry vs. happy faces) were assessed at pretreatment and again following 10 sessions of CBT in the GAD group and a comparable waiting period in the HC group. RESULTS: At pretreatment, GAD participants displayed blunted responses in the amygdala, insula, and anterior cingulate to the happy face-processing comparison condition, and greater amygdalo-insular connectivity. CBT was associated with attenuated amygdalar and subgenual anterior cingulate activation to fear/angry faces and heightened insular responses to the happy face comparison condition, but had no apparent effects on connectivity. Pre-treatment abnormalities and treatment-related changes were not associated with symptoms of worry. LIMITATIONS: There was no active control condition (e.g., treatment waitlist) for comparison of treatment effects. CONCLUSIONS: Taken together, these results provide evidence for a dual-process psychotherapeutic model of neural systems changes in GAD in which cingulo-amygdalar reactivity to threat-cues is attenuated while insular responses to positive facial emotions are potentiated. Future work is needed to determine the clinical implications of these changes and their specificity to CBT.

The effects of temporal unpredictability in anticipation of negative events in combat veterans with PTSD.

BACKGROUND: Exposure to psychological stress during combat can lead to posttraumatic stress disorder (PTSD). Anticipation of aversive events is often associated with an intense emotional state in individuals with PTSD. Both the valence (i.e., positive or negative) of the anticipated event and the degree of temporal predictability (i.e., one's ability to predict when an event will occur) have profound effects on an individual's emotional experience. This investigation tested the hypothesis that individuals with combat-related PTSD would show increased activation in the insula and related emotion-processing circuitry when anticipating emotionally significant events such as portrayed in combat-related images, and this heighted response within the insula would be particularly enhanced during temporal unpredictability. METHODS: About 15 male veterans with PTSD and 15 male veterans with combat-exposure but no current or lifetime history of PTSD (combat exposed controls/CEC) performed a temporal unpredictability anticipation task of unpleasant (combat-related) and pleasant images during fMRI. RESULTS: As expected, greater activation in the bilateral anterior insulae was observed in the PTSD versus the CEC subjects during anticipation of combat-related images when the anticipatory period was of uncertain duration (p<0.05). Furthermore, activation in the right anterior insula was related to greater perceived threat in the CEC group (ρ=0.619). LIMITATIONS: The current study looks only at combat-related PTSD in a modest preliminary sized sample. CONCLUSIONS: These findings suggest that an excessive anticipatory reaction in individuals with PTSD to temporally unpredictable aversive stimulus may relate to greater perceived threat. These findings are concordant with psychological models of PTSD that focus on the association of PTSD with the experience of decreased predictability and control.

Young adults at risk for stimulant dependence show reward dysfunction during reinforcement-based decision making.

BACKGROUND: While stimulant-dependent individuals continue to make risky decisions, in spite of poor outcomes, much less is known about decision-making characteristics of occasional stimulant users (OSU) at risk for developing stimulant dependence. This study examines whether OSU exhibit inefficient learning and execution of reinforced decision-outcome contingencies. METHODS: Occasional stimulant users (n = 161) and stimulant-naïve comparison subjects (CTL) (n = 48) performed a Paper Scissors Rock task during functional magnetic resonance imaging. Selecting a particular option was associated with a predetermined probability of winning, which was altered repeatedly to examine neural and behavioral characteristics of reinforced contingencies. RESULTS: Occasional stimulant users displayed greater anterior insula, inferior frontal gyrus, and dorsal striatum activation than CTL during late trials when contingencies were familiar (as opposed to being learned) in the presence of comparable behavioral performance in both groups. Follow-up analyses demonstrated that during late trials: 1) OSU with high cannabis use displayed greater activation in these brain regions than CTL, whereas OSU with low cannabis use did not differ from the other two groups; and 2) OSU preferring cocaine exhibited greater anterior insula, inferior frontal gyrus, and dorsal striatum activation than CTL and also displayed higher activation in the former two regions than OSU who preferred prescription stimulants. CONCLUSIONS: Occasional stimulant users exhibit inefficient resource allocation during the execution of reinforced contingencies that may be a result of additive effects of cocaine and cannabis use. A critical next step is to establish whether this inefficiency predicts transition to stimulant dependence.

Neural functional and structural correlates of childhood maltreatment in women with intimate-partner violence-related posttraumatic stress disorder.

Childhood maltreatment (CM) is a strong risk factor for development of posttraumatic stress disorder (PTSD) upon adult exposure to extreme adverse events. However, the neural underpinnings of this relationship are not well understood. Here, we test the hypothesis that severity of CM history is positively correlated with emotion-processing limbic and prefrontal brain activation/connectivity and negatively correlated with prefrontal gray matter volumes in women with PTSD due to intimate-partner violence (IPV-PTSD). Thirty-three women with IPV-PTSD underwent structural and functional magnetic resonance imaging while completing a facial emotion processing task. Multivariate regressions examined the relationship of CM to patterns of activation, connectivity, and gray matter volumes. CM severity was: (a) positively correlated with ventral ACC activation while processing angry faces; (b) negatively correlated with dorsal ACC and insula activation while processing fear and angry faces, arising from positive correlations with the shape-matching baseline; (c) positively correlated with limbic-prefrontal connectivity while processing fear faces but negatively correlated with amygdalo-insular connectivity while processing fear and angry; and (d) negatively correlated with prefrontal gray matter volumes. These results suggest CM exposure may account for variability in limbic/prefrontal brain function and prefrontal structure in adulthood PTSD and offer one potential mechanism through which CM confers risk to future development of PTSD.