An insula-driven network computes decision uncertainty and promotes abstinence in chronic cocaine users.

The anterior insular cortex (AIC) and its interconnected brain regions have been associated with both addiction and decision-making under uncertainty. However, the causal interactions in this uncertainty-encoding neurocircuitry and how these neural dynamics impact relapse remain elusive. Here, we used model-based fMRI to measure choice uncertainty in a motor decision task in 61 individuals with cocaine use disorder (CUD) and 25 healthy controls. CUD participants were assessed before discharge from a residential treatment program and followed for up to 24 weeks. We found that choice uncertainty was tracked by the AIC, dorsal anterior cingulate cortex (dACC) and ventral striatum (VS), across participants. Stronger activations in these regions measured pre-discharge predicted longer abstinence after discharge in individuals with CUD. Dynamic causal modeling revealed an AIC-to-dACC-directed connectivity modulated by uncertainty in controls, but a dACC-to-AIC connectivity in CUD participants. This reversal was mostly driven by early relapsers (<30 days). Furthermore, CUD individuals who displayed a stronger AIC-to-dACC excitatory connection during uncertainty encoding remained abstinent for longer periods. These findings reveal a critical role of an AIC-driven, uncertainty-encoding neurocircuitry in protecting against relapse and promoting abstinence.

Word-finding impairment in veterans of the 1991 Persian Gulf War.

Approximately one quarter of 1991 Persian Gulf War Veterans experience cognitive and physiological sequelae that continue to be unexplained by known medical or psychological conditions. Difficulty coming up with words and names, familiar before the war, is a hallmark of the illness. Three Gulf War Syndrome subtypes have been identified and linked to specific war-time chemical exposures. The most functionally impaired veterans belong to the Gulf War Syndrome 2 (Syndrome 2) group, for which subcortical damage due to toxic nerve gas exposure is the suspected cause. Subcortical damage is often associated with specific complex language impairments, and Syndrome 2 veterans have demonstrated poorer vocabulary relative to controls. 11 Syndrome 1, 16 Syndrome 2, 9 Syndrome 3, and 14 age-matched veteran controls from the Seabees Naval Construction Battalion were compared across three measures of complex language. Additionally, functional magnetic resonance imaging (fMRI) was collected during a covert category generation task, and whole-brain functional activity was compared between groups. Results demonstrated that Syndrome 2 veterans performed significantly worse on letter and category fluency relative to Syndrome 1 veterans and controls. They also exhibited reduced activity in the thalamus, putamen, and amygdala, and increased activity in the right hippocampus relative to controls. Syndrome 1 and Syndrome 3 groups tended to show similar, although smaller, differences than the Syndrome 2 group. Hence, these results further demonstrate specific impairments in complex language as well as subcortical and hippocampal involvement in Syndrome 2 veterans. Further research is required to determine the extent of language impairments in this population and the significance of altered neurologic activity in the aforementioned brain regions with the purpose of better characterizing the Gulf War Syndromes.

Interaction between early life stress and alcohol dependence on neural stress reactivity.

Stress response biologic systems are altered in alcohol-dependent individuals. Early life stress (ELS) is associated with a heightened risk of alcohol dependence, presumably because of stress-induced neuroplastic changes. This study was designed to assess the contribution of ELS to a stress-induced neural response in alcohol-dependent participants. Fifteen alcohol-dependent men abstinent for 3-5 weeks and 15 age- and race-matched healthy controls were studied. Anticipatory anxiety was induced by a conditioned stimulus paired with an uncertain physically painful unconditioned stressor. Neural response was assessed with functional magnetic resonance imaging. ELS was assessed with the Childhood Adversity Interview. There was a significant interaction between ELS and group on blood-oxygen-level-dependent (BOLD) amplitude during anticipatory anxiety in the right amygdala and bilateral orbitofrontal cortex, posterior putamen and insula. Higher ELS scores were associated with decreased BOLD amplitude during anticipatory anxiety in alcohol-dependent, but not control, participants. These findings suggest that ELS interacts with alcohol dependence to induce a muted cortico-striatal response to high threat stimuli. Allostatic changes due to both ELS and excessive alcohol use may jointly induce persistent changes in the neural response to acute stressors.

Anteroposterior perfusion heterogeneity in human hippocampus measured by arterial spin labeling MRI.

Measurements of blood flow in the human hippocampus are complicated by its relatively small size, unusual anatomy and patterns of blood supply. Only a handful of arterial spin labeling (ASL) MRI articles have reported regional cerebral blood flow (rCBF) values for the human hippocampus. Numerous reports have found heterogeneity in a number of other physiological and biochemical parameters along the longitudinal hippocampal axis. There is, however, only one ASL study of perfusion properties as a function of anteroposterior location in the hippocampus, reporting that rCBF is lower and the arterial transit time (ATT) is longer in the anterior hippocampus than in the posterior hippocampus of the rat brain. The purpose of this article was to measure ATT and rCBF in anterior, middle and posterior normal adult human hippocampus. To better distinguish anteroposterior perfusion heterogeneity in the hippocampus, a modified ASL method, called Orthogonally Positioned Tagging Imaging Method for Arterial Labeling with Flow-sensitive Alternating Inversion Recovery (OPTIMAL FAIR), was developed that provides high in-plane resolution with oblique coronal imaging slices perpendicular to the long axis of the hippocampus to minimize partial volume effects. Perfusion studies performed with this modified FAIR method at 3 T indicated that anterior, middle and posterior human hippocampus segments have unique transit time and rCBF values. Of these three longitudinal hippocampal regions, the middle hippocampus has the highest perfusion and the shortest transit time and the anterior hippocampus has the lowest perfusion and the longest transit time. Copyright © 2013 John Wiley & Sons, Ltd.

Altered neural processing of threat in alcohol-dependent men.

BACKGROUND: Stress-response biological systems are altered in alcohol-dependent individuals and are reported to predict future relapse. This study was designed to assess neural disruptions in alcohol-dependent participants when exposed to a conditioned stimulus (CS) warning of the impending onset of a universal, nonpersonalized stressor. METHODS: Fifteen alcohol-dependent men abstinent for 3 to 5 weeks and 15 age- and race-similar healthy controls were studied. Anticipatory anxiety was induced by a CS paired with an uncertain, physically painful unconditioned stressor. Neural response was assessed using functional magnetic resonance imaging. RESULTS: Both groups experienced significant, similar levels of anticipatory anxiety in response to the high-threat relative to the low-threat CS. Whereas control participants markedly increased the blood oxygen level-dependent (BOLD) amplitude in cortical-limbic-striatal regions during the high-threat, relative to low-threat, stimulus, alcohol-dependent participants decreased BOLD amplitude in the pregenual anterior cingulate cortex (pgACC), medial prefrontal cortex (mPFC), medial orbitofrontal cortex, posterior cingulate cortex (PCC), bilateral parietal/occipital cortex, and right hippocampus. Alcohol-dependent participants significantly deactivated pgACC/mPFC and PCC clusters, relative to controls, during the high- versus low-threat stimulus. This difference was due to a decrease in %BOLD amplitude during the high-threat stimulus in the alcohol-dependent, but not the control, participants. CONCLUSIONS: Alcohol-dependent men show cortical-limbic-striatal deactivation during anticipatory anxiety, particularly in regions associated with emotional regulation. These findings suggest a lack of engagement of affective regulatory mechanisms during high-stress situations in alcohol-dependent men.

Dynamic physostigmine effects on hippocampus perfusion.

PURPOSE: To characterize the dynamic response of hippocampus blood flow to physostigmine infusion and to determine an infusion duration sufficiently long for robust detection of effects with arterial spin labeling (ASL) and sufficiently short to avoid peripheral side effects of physostigmine. MATERIALS AND METHODS: Two female (49 ± 15 years) and nine male (53 ± 13 years) subjects were studied to determine the time course of the physostigmine effect on hippocampus blood flow with ASL perfusion imaging during 20 minutes of baseline, 30 minutes of physostigmine infusion at 1.0 mg/hr, and 70 minutes of recovery. RESULTS: Hippocampus perfusion decreased steadily over the course of the infusion, with the reduction in flow becoming significant after 20 minutes of infusion, reaching lowest levels near the end of infusion, and remaining significantly low and stable in the 70-minute recovery period. Percentage changes of hippocampus perfusion were -13.3%, -13.4%, and -13.4% for left, right, and bilateral hippocampus, respectively, at the end of infusion. CONCLUSION: At a dose rate of 1.0 mg/hr it is feasible to use an infusion time as short as 20 minutes, performing perfusion imaging up to an hour after physostigmine infusion is discontinued, to minimize chances for adverse side effects.

Simplifying complex fault data for systems-level analysis: Earthquake geology inputs for U.S. NSHM 2023.

As part of the U.S. National Seismic Hazard Model (NSHM) update planned for 2023, two databases were prepared to more completely represent Quaternary-active faulting across the western United States: the NSHM23 fault sections database (FSD) and earthquake geology database (EQGeoDB). In prior iterations of NSHM, fault sections were included only if a field-measurement-derived slip rate was estimated along a given fault. By expanding this inclusion criteria, we were able to assess a larger set of faults for use in NSHM23. The USGS Quaternary Fault and Fold Database served as a guide for assessing possible additions to the NSHM23 FSD. Reevaluating available data from published sources yielded an increase of fault sections from ~650 faults in NSHM18 to ~1,000 faults proposed for use in NSHM23. EQGeoDB, a companion dataset linked to NSHM23 FSD, contains geologic slip rate estimates for fault sections included in FSD. Together, these databases serve as common input data used in deformation modeling, earthquake rupture forecasting, and additional downstream uses in NSHM development.

Hippocampal dysfunction in Gulf War veterans: investigation with ASL perfusion MR imaging and physostigmine challenge.

PURPOSE: To determine, with arterial spin labeling (ASL) perfusion magnetic resonance (MR) imaging and physostigmine challenge, if abnormal hippocampal blood flow in ill Gulf War veterans persists 11 years after initial testing with single photon emission computed tomography and nearly 20 years after the 1991 Gulf War. MATERIALS AND METHODS: The local institutional review board approved this HIPAA-compliant study. Veterans were screened for contraindications and gave written informed consent before the study. In a semiblinded retrospective protocol, veterans in three Gulf War illness groups-syndrome 1 (impaired cognition), syndrome 2 (confusion-ataxia), and syndrome 3 (central neuropathic pain)-and a control group received intravenous infusions of saline in an initial session and physostigmine in a second session, 48 hours later. Each infusion was followed by measurement of hippocampal regional cerebral blood flow (rCBF) with pulsed ASL. A mixed-effects linear model adjusted for age was used to test for differences in rCBF after the cholinergic challenge across the four groups. RESULTS: Physostigmine significantly decreased hippocampal rCBF in control subjects (P < .0005) and veterans with syndrome 1 (P < .05) but significantly increased hippocampal rCBF in veterans with syndrome 2 (P < .005) and veterans with syndrome 3 (P < .002). The abnormal increase in rCBF was found to have progressed to the left hippocampus of the veterans with syndrome 2 and to both hippocampi of the veterans with syndrome 3. CONCLUSION: Chronic hippocampal perfusion dysfunction persists or worsens in veterans with certain Gulf War syndromes. ASL MR imaging examination of hippocampal rCBF in a cholinergic challenge experiment may be useful as a diagnostic test for this condition.

Improved quantification of brain perfusion using FAIR with active suppression of superior tagging (FAIR ASST).

PURPOSE: To address two problems for perfusion studies in the middle or inferior brain regions: (1) to reduce venous artifacts due to the intrinsic superior labeling of FAIR; (2) to alleviate the discrepancy of the existence of both superior and inferior boluses, but with only the inferior bolus having a temporally defined bolus width with Q2TIPs or QUIPSS. MATERIALS AND METHODS: Superior tagging suppression methods for FAIR with different combinations of pre- and postinversion superior saturation pulses were evaluated and compared with FAIR with Q2TIPS for producing perfusion maps of superior, middle, and inferior brain regions. RESULTS: One preinversion plus two postinversion superior saturation radio frequency pulses effectively suppressed the superior tagging of FAIR and sufficiently eliminated venous artifacts without negative effects, avoiding the overestimations of cerebral blood flow that can occur in FAIR. CONCLUSION: FAIR ASST improves FAIR with Q2TIPS and provides more reliable and accurate blood flow estimations for perfusion studies of middle and lower brain regions. FAIR ASST confers the advantages of asymmetric PASL techniques, such as PICORE, in which only the inferiorly labeled blood is used for perfusion quantification, to the symmetric PASL technique FAIR, while preserving the robustness of FAIR against MT effects.

Changing impacts of Alaska-Aleutian subduction zone tsunamis in California under future sea-level rise.

The amplification of coastal hazards such as distant-source tsunamis under future relative sea-level rise (RSLR) is poorly constrained. In southern California, the Alaska-Aleutian subduction zone has been identified as an earthquake source region of particular concern for a worst-case scenario distant-source tsunami. Here, we explore how RSLR over the next century will influence future maximum nearshore tsunami heights (MNTH) at the Ports of Los Angeles and Long Beach. Earthquake and tsunami modeling combined with local probabilistic RSLR projections show the increased potential for more frequent, relatively low magnitude earthquakes to produce distant-source tsunamis that exceed historically observed MNTH. By 2100, under RSLR projections for a high-emissions representative concentration pathway (RCP8.5), the earthquake magnitude required to produce >1 m MNTH falls from ~Mw9.1 (required today) to Mw8.0, a magnitude that is ~6.7 times more frequent along the Alaska-Aleutian subduction zone.

Selective detrending method for reducing task-correlated motion artifact during speech in event-related FMRI.

Task-correlated motion artifacts that occur during functional magnetic resonance imaging can be mistaken for brain activity. In this work, a new selective detrending method for reduction of artifacts associated with task-correlated motion (TCM) during speech in event-related functional magnetic resonance imaging is introduced and demonstrated in an overt word generation paradigm. The performance of this new method is compared with that of three existing methods for reducing artifacts because of TCM: (1) motion parameter regression, (2) ignoring images during speech, and (3) detrending time course datasets of signal components related to TCM (deduced from artifact corrupted voxels). The selective detrending method outperforms the other three methods in reducing TCM artifacts and in retaining blood oxygenation level dependent signal.

Gulf War illness associated with abnormal auditory P1 event-related potential: Evidence of impaired cholinergic processing replicated in a national sample.

Our team previously reported event-related potential (ERP) and hyperarousal patterns from a study of one construction battalion of the U.S. Naval Reserve who served during the 1991 Persian Gulf War. We sought to replicate these findings in a sample that was more representative of the entire Gulf War-era veteran population, including male and female participants from four branches of the military. We collected ERP data from 40 veterans meeting Haley criteria for Gulf War syndromes 1-3 and from 22 matched Gulf War veteran controls while they performed an auditory oddball task. Reports of hyperarousal from the ill veterans were significantly greater than those from the control veterans, and P1 amplitudes in Syndromes 2 and 3 were significantly higher than P1 amplitudes in Syndrome 1, replicating our previous findings. Many of the contributors to the generation of the P1 potential are also involved in the regulation of arousal and are modulated by cholinergic and dopaminergic systems-two systems whose dysfunction has been implicated in Gulf War illness. These differences among the three syndrome groups where their means were on either side of controls is a replication of our previous ERP study and is consistent with previous imaging studies of this population.

Neural substrates related to auditory working memory comparisons in dyslexia: an fMRI study.

Adult readers with developmental phonological dyslexia exhibit significant difficulty comparing pseudowords and pure tones in auditory working memory (AWM). This suggests deficient AWM skills for adults diagnosed with dyslexia. Despite behavioral differences, it is unknown whether neural substrates of AWM differ between adults diagnosed with dyslexia and normal readers. Prior neuroimaging of adults diagnosed with dyslexia and normal readers, and post-mortem findings of neural structural anomalies in adults diagnosed with dyslexia support the hypothesis of atypical neural activity in temporoparietal and inferior frontal regions during AWM tasks in adults diagnosed with dyslexia. We used fMRI during two binaural AWM tasks (pseudowords or pure tones comparisons) in adults diagnosed with dyslexia (n = 11) and normal readers (n = 11). For both AWM tasks, adults diagnosed with dyslexia exhibited greater activity in left posterior superior temporal (BA 22) and inferior parietal regions (BA 40) than normal readers. Comparing neural activity between groups and between stimuli contrasts (pseudowords vs. tones), adults diagnosed with dyslexia showed greater primary auditory cortex activity (BA 42; tones > pseudowords) than normal readers. Thus, greater activity in primary auditory, posterior superior temporal, and inferior parietal cortices during linguistic and non-linguistic AWM tasks for adults diagnosed with dyslexia compared to normal readers indicate differences in neural substrates of AWM comparison tasks.

Memory and functional brain differences in a national sample of U.S. veterans with Gulf War Illness.

Roughly 26-32% of U. S. veterans who served in the 1991 Persian Gulf War report suffering from chronic health problems. Memory complaints are regularly reported by ill Gulf War veterans (GWV), but limited data verify their complaints. This study investigated episodic memory and brain function in a nationally representative sample of GWV, using a face-name memory task and functional magnetic resonance imaging during encoding. A syndrome classification system was used to subdivide ill GWV into the three major Gulf War Illness syndrome types, "impaired cognition" (GWV-1), "confusion ataxia" (GWV-2), and "central pain" (GWV-3). Memory and brain function of ill GWV were contrasted to deployed and nondeployed well GWV controls (GWV-C). Ill GWV exhibited impaired memory function relative to GWV-C but the patterns of functional brain differences varied. Brain activation differentiated the GWV-C from the ill GWV. The different syndrome types also differed from one another in several brain regions. Additionally, the current study was the first to observe differences in brain function between deployed and nondeployed GWV-C. These results provide (1) evidence of memory impairment in ill GWV and differentiate the syndrome types at a functional neurobiological level, and (2) the role of deployment in the war on brain function.

Functional magnetic resonance imaging before and after aphasia therapy: shifts in hemodynamic time to peak during an overt language task.

BACKGROUND AND PURPOSE: Comparing the temporal characteristics of hemodynamic responses in activated cortical regions of aphasic patients before and after therapy would provide insight into the relationship between improved task performance and changes in blood oxygenation level-dependent (BOLD) functional MRI (fMRI) signal. This study investigated differences in the time to peak (TTP) of hemodynamic responses in activated regions of interest (ROIs), before and after therapy, and related them to changes in task performance. METHODS: Three aphasic patients and 3 controls overtly generated a single exemplar in response to a category. For the patients, TTP of hemodynamic responses in selected ROIs was compared before and after language therapy. The timing differences between auditory cues and verbal responses were compared with TTP differences between auditory and motor cortices. RESULTS: The selected ROIs were significantly activated in both aphasic patients and controls during overt word generation. In the aphasic patients, both the timing difference from auditory cues to verbal responses and the TTP difference between auditory and motor cortices decreased after rehabilitation, becoming similar to the values found in controls. CONCLUSIONS: Findings indicate that (1) rehabilitation increased the speed of word-finding processes; (2) TTP analysis was sensitive to this functional change and can be used to represent improvement in behavior; and (3) it is important to monitor the behavioral performance that might correlate with the temporal pattern of the hemodynamic response.

Central representation of visceral and cutaneous hypersensitivity in the irritable bowel syndrome.

We have previously shown that irritable bowel syndrome (IBS) patients have both visceral and cutaneous hyperalgesia. The neural mechanisms of these forms of hyperalgesia were further characterized by comparing cortical processing of both rectal distension (35, 55mmHg) and cutaneous heat nociceptive stimuli (foot immersion in 45 and 47 degrees C water bath) in IBS patients and in a group of healthy age/sex-matched controls. Our approach relied on functional magnetic resonance imaging neuroimaging analyses in which brain activation in age/sex-matched control subjects was subtracted from that found in IBS patients. These analyses revealed that both rectal distension and cutaneous heat stimuli evoked greater neural activity in several brain regions of IBS patients in comparison to age/sex-matched control subjects. These include those related to early stages of somatosensory processing (e.g. thalamus, somatosensory cortex) as well as those more related to cognitive and affective processing (insular, anterior cingulate, posterior cingulate, prefrontal cortex). Thus, our results support the hypothesis that hyperalgesia of IBS is manifested by increased somatosensory processing at all cortical levels. This was found to be the case not only for visceral hyperalgesia but also for cutaneous heat hyperalgesia, a likely form of secondary hyperalgesia. Furthermore, visceral and heat hyperalgesia were accompanied by increased neural activity within the same brain structures. These results support the hypothesis that visceral and cutaneous hyperalgesia in IBS patients is related to increased afferent processing in pathways ascending to the brain rather than to selectively increased activity at higher cortical levels (e.g. limbic and frontal cortical areas).

Quantifying cerebellum grey matter and white matter perfusion using pulsed arterial spin labeling.

To facilitate quantification of cerebellum cerebral blood flow (CBF), studies were performed to systematically optimize arterial spin labeling (ASL) parameters for measuring cerebellum perfusion, segment cerebellum to obtain separate CBF values for grey matter (GM) and white matter (WM), and compare FAIR ASST to PICORE. Cerebellum GM and WM CBF were measured with optimized ASL parameters using FAIR ASST and PICORE in five subjects. Influence of volume averaging in voxels on cerebellar grey and white matter boundaries was minimized by high-probability threshold masks. Cerebellar CBF values determined by FAIR ASST were 43.8 ± 5.1 mL/100 g/min for GM and 27.6 ± 4.5 mL/100 g/min for WM. Quantitative perfusion studies indicated that CBF in cerebellum GM is 1.6 times greater than that in cerebellum WM. Compared to PICORE, FAIR ASST produced similar CBF estimations but less subtraction error and lower temporal, spatial, and intersubject variability. These are important advantages for detecting group and/or condition differences in CBF values.

Visual event-related potentials as markers of hyperarousal in Gulf War illness: evidence against a stress-related etiology.

An exaggerated response to emotional stimuli is among the many symptoms widely reported by veterans of the 1991 Persian Gulf War. These symptomologies have been attributed to damage and dysfunction associated with deployment-related exposures. We collected event-related potential data from 22 veterans meeting Haley criteria for Gulf War (GW) Syndromes 1-3 and from 8 matched GW veteran controls, who were deployed but not symptomatic, while they performed a visual three-condition oddball task where images authenticated to be associated with the 1991 Persian Gulf War were the distractor stimuli. Hyperarousal reported by ill veterans was significantly greater than that by control veterans, but this was not paralleled by higher amplitude P3a in their ERP responses to GW-related distractor stimuli. Whereas previous studies of PTSD patients have shown higher amplitude P3b responses to target stimuli that are placed amid trauma-related nontarget stimuli, ill veterans in this study showed P3b amplitudes to target stimuli - placed amid GW-related nontarget stimuli - that were significantly lower than those of the control group. Hyperarousal scores reliably predicted P3b, but not P3a, amplitudes. Although many factors may contribute to P3b amplitude differences - most notably depression and poor sleep quality, symptoms that are prevalent in the GW syndrome groups - our findings in context of previous studies on this population are consistent with the contention that dysfunction in cholinergic and dopaminergic neurotransmitter systems, and in white matter and basal ganglia may be contributing to impairments in GW veterans.

Striatal-limbic activation is associated with intensity of anticipatory anxiety.

Anxiety experienced in anticipation of impending aversive events induces striatal-limbic activation. However, previous functional magnetic imaging (fMRI) studies of anticipatory anxiety have utilized post-test measures of anxiety, making a direct association between neural activation and distress problematic. This paradigm was designed to assess the blood-oxygen-level-dependent (BOLD) response to an aversive conditioned stimulus while simultaneously measuring subjective anxiety. Fifteen male healthy subjects (45.5±8.5 years old) were studied. A high-threat conditioned stimulus (CS) was paired with either an unpredictable, highly aversive (painful) or non-aversive (non-painful) unconditioned stimulus and compared to a low-threat CS paired with a predictable, non-aversive stimulus. Neural response was assessed with fMRI, and subjective anxiety (1-4) was recorded upon the presentation of each CS. High subjective ratings of real-time anticipatory anxiety (2-4), relative to low anticipatory anxiety (1), elicited increased activation in the bilateral striatum, bilateral orbital frontal cortex, left anterior insula, and anterior cingulate cortex (ACC) and decreased activation in the posterior cingulate cortex (PCC). The amplitude of BOLD signal change generally paralleled the subjective rating of anxiety. Real-time measures of anticipatory anxiety confirm previous reports, using post-test measures of anxiety, of striatal-limbic activation during anticipatory anxiety while simultaneously demonstrating an increase in BOLD response in parallel with heightened anxiety.