Neurons in the Doppler-shifted constant frequency processing (DSCF) area in the primary auditory cortex of mustached bats, Pteronotus parnellii, are multifunctional, responding both to echolocation and communication sounds. Simultaneous presentation of a DSCF neuron's best low and high frequencies (BF_low and BF_high, respectively) facilitates its response. BF_low corresponds to a frequency in the frequency-modulated (FM) component of the first harmonic in the echolocation pulse, and BF_high corresponds to the constant frequency (CF) component in the second harmonic of the echo. We systematically varied the slopes, bandwidths, and central frequencies of FMs traversing the BF_high region to arrive at the “best FM” for single DSCF neurons. We report that nearly half (46%) of DSCF neurons preferred linear FMs to CFs and average response magnitude to FMs was not significantly less ( P = 0.08) than that to CFs at BF_high when each test stimulus was paired with a CF at BF_low. For linear FMs ranging in slope from 0.04 to 4.0 kHz/ms and in bandwidth from 0.44 to 7.88 kHz, the majority of DSCF neurons preferred upward (55%) to downward (21%) FMs. Central frequencies of the best FMs were typically close to but did not always match a neuron's BF_high. Neurons exhibited combination-sensitivity to “call fragments” (calls that were band-pass filtered in the BF_high region) paired with their BF_low. Our data show a close match between the modulation direction of a neuron's best FM and that of its preferred call fragment. These response properties show that DSCF neurons extract multiple parameters of FMs and are specialized for processing both FMs for communication and CFs for echolocation.

Gulf War Illness affects 25–30% of American veterans deployed to the 1990–91 Persian Gulf War and is characterized by cognitive post-exertional malaise following physical effort. Gulf War Illness remains controversial since cognitive post-exertional malaise is also present in the more common Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. An objective dissociation between neural substrates for cognitive post-exertional malaise in Gulf War Illness and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome would represent a biological basis for diagnostically distinguishing these two illnesses. Here, we used functional magnetic resonance imaging to measure neural activity in healthy controls and patients with Gulf War Illness and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome during an N-back working memory task both before and after exercise. Whole brain activation during working memory (2-Back > 0-Back) was equal between groups prior to exercise. Exercise had no effect on neural activity in healthy controls yet caused deactivation within dorsal midbrain and cerebellar vermis in Gulf War Illness relative to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome patients. Further, exercise caused increased activation among Myalgic Encephalomyelitis/Chronic Fatigue Syndrome patients within the dorsal midbrain, left operculo-insular cortex (Rolandic operculum) and right middle insula. These regions-of-interest underlie threat assessment, pain, interoception, negative emotion and vigilant attention. As they only emerge post-exercise, these regional differences likely represent neural substrates of cognitive post-exertional malaise useful for developing distinct diagnostic criteria for Gulf War Illness and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), Gulf War Illness (GWI) and control subjects underwent fMRI during difficult cognitive tests performed before and after submaximal exercise provocation (Washington 2020). Exercise caused increased activation in ME/CFS but decreased activation for GWI in the dorsal midbrain, left Rolandic operculum and right middle insula. Midbrain and isthmus nuclei participate in threat assessment, attention, cognition, mood, pain, sleep, and autonomic dysfunction. Methods: Activated midbrain nuclei were inferred by a re-analysis of data from 31 control, 36 ME/CFS and 78 GWI subjects using a seed region approach and the Harvard Ascending Arousal Network. Results: Before exercise, control and GWI subjects showed greater activation during cognition than ME/CFS in the left pedunculotegmental nucleus. Post exercise, ME/CFS subjects showed greater activation than GWI ones for midline periaqueductal gray, dorsal and median raphe, and right midbrain reticular formation, parabrachial complex and locus coeruleus. The change between days (delta) was positive for ME/CFS but negative for GWI, indicating reciprocal patterns of activation. The controls had no changes. Conclusions: Exercise caused the opposite effects with increased activation in ME/CFS but decreased activation in GWI, indicating different pathophysiological responses to exertion and mechanisms of disease. Midbrain and isthmus nuclei contribute to postexertional malaise in ME/CFS and GWI.

Gulf War Illness affects 25–32% of veterans from the 1990–91 Persian Gulf War. Post-exertional malaise with cognitive dysfunction, pain and fatigue following physical and/or mental effort is a defining feature of Gulf War Illness. We modelled post-exertional malaise by assessing changes in functional magnetic resonance imaging at 3T during an N-Back working memory task performed prior to a submaximal bicycle stress test and after an identical stress test 24 h later. Serial trends in postural changes in heart rate between supine and standing defined three subgroups of veterans with Gulf War Illness: Postural Orthostatic Tachycardia Syndrome (GWI-POTS, 15%, n = 11), Stress Test Associated Reversible Tachycardia (GWI-START, 31%, n = 23) and Stress Test Originated Phantom Perception (GWI-STOPP, no postural tachycardia, 54%, n = 46). Before exercise, there were no differences in blood oxygenation level-dependent activity during the N-Back task between control (n = 31), GWI-START, GWI-STOPP and GWI-POTS subgroups. Exercise had no effects on blood oxygenation level-dependent activation in controls. GWI-START had post-exertional deactivation of cerebellar dentate nucleus and vermis regions associated with working memory. GWI-STOPP had significant activation of the anterior supplementary motor area that may be a component of the anterior salience network. There was a trend for deactivation of the vermis in GWI-POTS after exercise. These patterns of cognitive dysfunction were apparent in Gulf War Illness only after the exercise stressor. Mechanisms linking the autonomic dysfunction of Stress Test Associated Reversible Tachycardia and Postural Orthostatic Tachycardia Syndrome to cerebellar activation, and Stress Test Originated Phantom Perception to cortical sensorimotor alterations, remain unclear but may open new opportunities for understanding, diagnosing and treating Gulf War Illness.

Background: Gulf War Illness (GWI) and Chronic Fatigue Syndrome (CFS) are two debilitating disorders that share similar symptoms of chronic pain, fatigue, and exertional exhaustion after exercise. Many physicians continue to believe that both are psychosomatic disorders and to date no underlying etiology has been discovered. As such, uncovering objective biomarkers is important to lend credibility to criteria for diagnosis and to help differentiate the two disorders. Methods: We assessed cognitive differences in 80 subjects with GWI and 38 with CFS by comparing corresponding fMRI scans during 2-back working memory tasks before and after exercise to model brain activation during normal activity and after exertional exhaustion, respectively. Voxels were grouped by the count of total activity into the Automated Anatomical Labeling (AAL) atlas and used in an “ensemble” series of machine learning algorithms to assess if a multi-regional pattern of differences in the fMRI scans could be detected. Results: A K-Nearest Neighbor (70%/81%), Linear Support Vector Machine (SVM) (70%/77%), Decision Tree (82%/82%), Random Forest (77%/78%), AdaBoost (69%/81%), Naïve Bayes (74%/78%), Quadratic Discriminant Analysis (QDA) (73%/75%), Logistic Regression model (82%/82%), and Neural Net (76%/77%) were able to differentiate CFS from GWI before and after exercise with an average of 75% accuracy in predictions across all models before exercise and 79% after exercise. An iterative feature selection and removal process based on Recursive Feature Elimination (RFE) and Random Forest importance selected 30 regions before exercise and 33 regions after exercise that differentiated CFS from GWI across all models, and produced the ultimate best accuracies of 82% before exercise and 82% after exercise by Logistic Regression or Decision Tree by a single model, and 100% before and after exercise when selected by any six or more models. Differential activation on both days included the right anterior insula, left putamen, and bilateral orbital frontal, ventrolateral prefrontal cortex, superior, inferior, and precuneus (medial) parietal, and lateral temporal regions. Day 2 had the cerebellum, left supplementary motor area and bilateral pre- and post-central gyri. Changes between days included the right Rolandic operculum switching to the left on Day 2, and the bilateral midcingulum switching to the left anterior cingulum. Conclusion: We concluded that CFS and GWI are significantly differentiable using a pattern of fMRI activity based on an ensemble machine learning model.