Unravelling the influence of affective stimulation on functional neurological symptoms: a pilot experiment examining potential mechanisms.

BACKGROUND: Differences in affective processing have previously been shown in functional neurological disorder (FND); however, the mechanistic relevance is uncertain. We tested the hypotheses that highly arousing affective stimulation would result in elevated subjective functional neurological symptoms (FNS), and this would be associated with elevated autonomic reactivity. The possible influence of cognitive detachment was also explored. METHOD: Individuals diagnosed with FND (motor symptoms/seizures; n=14) and healthy controls (n=14) viewed Positive, Negative and Neutral images in blocks, while passively observing the stimuli ('Watch') or detaching themselves ('Distance'). The FND group rated their primary FNS, and all participants rated subjective physical (arousal, pain, fatigue) and psychological states (positive/negative affect, dissociation), immediately after each block. Skin conductance (SC) and heart rate (HR) were monitored continuously. RESULTS: FNS ratings were higher after Negative compared with Positive and Neutral blocks in the FND group (p=0.002, ηp 2=0.386); however, this effect was diminished in the Distance condition relative to the Watch condition (p=0.018, ηp 2=0.267). SC and/or HR correlated with FNS ratings in the Negative-Watch and Neutral-Distance conditions (r values=0.527-0.672, p values=0.006-0.035). The groups did not differ in subjective affect or perceived arousal (p values=0.541-0.919, ηp 2=<0.001-0.015). CONCLUSIONS: Emotionally significant events may exert an influence on FNS which is related to autonomic activation rather than altered subjective affect or perceived arousal. This influence may be modulated by cognitive detachment. Further work is needed to determine the relevance and neural bases of these processes in specific FND phenotypes.

Etiological Factors and Symptom Triggers in Functional Motor Symptoms and Functional Seizures: A Pilot Investigation.

OBJECTIVE: This study examined etiological factors and symptom triggers of functional motor symptoms (FMS) or functional seizures (FS) and assessed potential relationships with relevant clinical features (i.e., functional symptoms, quality of life, and general functioning). METHODS: Seventeen participants with FMS or FS and 17 healthy control participants underwent an in-depth clinical interview and completed questionnaires assessing adverse life events, psychological and physical symptoms, alexithymia, autistic traits, illness perceptions, health-related quality of life (HRQoL), and work and social functioning. RESULTS: Participants with FMS or FS perceived various causes of the disorder, including physical symptoms (65%), emotional problems (53%), adverse life events (47%), and work-related factors (29%). Triggers of FMS and FS included physical activity or exertion (59%), stress and emotions (59%), sensory experiences (47%), and fatigue (41%). Compared with healthy control participants, participants with FMS or FS reported more adverse events during adolescence and higher levels of alexithymia, somatoform dissociation, psychological dissociation (disengagement, depersonalization, and derealization), anxiety, depression, and physical symptoms. Participants with FMS or FS had worse HRQoL than healthy control participants and impaired work and social functioning. There were inverse associations between HRQoL scores and somatoform dissociation, anxiety, and adverse life events. CONCLUSIONS: Participants with FMS or FS reported diverse biopsychosocial etiological factors and symptom triggers. Ongoing psychological symptoms and lifetime adverse experiences were associated with worse HRQoL. Future studies will examine these factors in larger samples of individuals with FMS or FS to better understand their shared and distinct etiological underpinnings.

The unforeseen future: Impacts of the COVID-19 pandemic on home video-EEG telemetry.

The coronavirus disease 2019 (COVID-19) pandemic had widespread impact on health care systems globally-particularly services arranged around elective admission and attendance such as epilepsy monitoring units and home video-EEG telemetry (HVET). Here, we review the ongoing impacts of the pandemic on HVET services among several different providers who used different initial models of HVET. We discuss the features of HVET that led to success in providing continued diagnostic services to patients with epilepsy and related disorders and through retrospective audit of our services demonstrate the high diagnostic yield of HVET. We reflect on this unforeseen future and its implications for other diagnostic techniques and approaches.

Seizure forecasting using minimally invasive, ultra-long-term subcutaneous EEG: Generalizable cross-patient models.

This study describes a generalized cross-patient seizure-forecasting approach using recurrent neural networks with ultra-long-term subcutaneous EEG (sqEEG) recordings. Data from six patients diagnosed with refractory epilepsy and monitored with an sqEEG device were used to develop a generalized algorithm for seizure forecasting using long short-term memory (LSTM) deep-learning classifiers. Electrographic seizures were identified by a board-certified epileptologist. One-minute data segments were labeled as preictal or interictal based on their relationship to confirmed seizures. Data were separated into training and testing data sets, and to compensate for the unbalanced data ratio in training, noise-added copies of preictal data segments were generated to expand the training data set. The mean and standard deviation (SD) of the training data were used to normalize all data, preserving the pseudo-prospective nature of the analysis. Different architecture classifiers were trained and tested using a leave-one-patient-out cross-validation method, and the area under the receiver-operating characteristic (ROC) curve (AUC) was used to evaluate the performance classifiers. The importance of each input signal was evaluated using a leave-one-signal-out method with repeated training and testing for each classifier. Cross-patient classifiers achieved performance significantly better than chance in four of the six patients and an overall mean AUC of 0.602 ± 0.126 (mean ± SD). A time in warning of 37.386% ± 5.006% (mean ± std) and sensitivity of 0.691 ± 0.068 (mean ± std) were observed for patients with better than chance results. Analysis of input channels showed a significant contribution (p < .05) by the Fourier transform of signals channels to overall classifier performance. The relative contribution of input signals varied among patients and architectures, suggesting that the inclusion of all signals contributes to robustness in a cross-patient classifier. These early results show that it is possible to forecast seizures training with data from different patients using two-channel ultra-long-term sqEEG.

Seizure forecasting using minimally invasive, ultra-long-term subcutaneous electroencephalography: Individualized intrapatient models.

OBJECTIVE: One of the most disabling aspects of living with chronic epilepsy is the unpredictability of seizures. Cumulative research in the past decades has advanced our understanding of the dynamics of seizure risk. Technological advances have recently made it possible to record pertinent biological signals, including electroencephalogram (EEG), continuously. We aimed to assess whether patient-specific seizure forecasting is possible using remote, minimally invasive ultra-long-term subcutaneous EEG. METHODS: We analyzed a two-center cohort of ultra-long-term subcutaneous EEG recordings, including six patients with drug-resistant focal epilepsy monitored for 46-230 days with median 18 h/day of recorded data, totaling >11 000 h of EEG. Total electrographic seizures identified by visual review ranged from 12 to 36 per patient. Three candidate subject-specific long short-term memory network deep learning classifiers were trained offline and pseudoprospectively on preictal (1 h before) and interictal (>1 day from seizures) EEG segments. Performance was assessed relative to a random predictor. Periodicity of the final forecasts was also investigated with autocorrelation. RESULTS: Depending on each architecture, significant forecasting performance was achieved in three to five of six patients, with overall mean area under the receiver operating characteristic curve of .65-.74. Significant forecasts showed sensitivity ranging from 64% to 80% and time in warning from 10.9% to 44.4%. Overall, the output of the forecasts closely followed patient-specific circadian patterns of seizure occurrence. SIGNIFICANCE: This study demonstrates proof-of-principle for the possibility of subject-specific seizure forecasting using a minimally invasive subcutaneous EEG device capable of ultra-long-term at-home recordings. These results are encouraging for the development of a prospective seizure forecasting trial with minimally invasive EEG.

Peri-ictal hypoxia is related to extent of regional brain volume loss accompanying generalized tonic-clonic seizures.

OBJECTIVES: Hypoxia, or abnormally low blood-oxygen levels, often accompanies seizures and may elicit brain structural changes in people with epilepsy which contribute to central processes underlying sudden unexpected death in epilepsy (SUDEP). The extent to which hypoxia may be related to brain structural alterations in this patient group remains unexplored. METHODS: We analyzed high-resolution T1-weighted magnetic resonance imaging (MRI) to determine brain morphometric and volumetric alterations in people with generalized tonic-clonic seizures (GTCS) recorded during long-term video-electroencephalography (VEEG), recruited from two sites (n = 22), together with data from age- and sex-matched healthy controls (n = 43). Subjects were sub-divided into those with mild/moderate (GTCS-hypox-mild/moderate, n = 12) and severe (GTCS-hypox-severe, n = 10) hypoxia, measured by peripheral oxygen saturation (SpO2 ) during VEEG. Whole-brain voxel-based morphometry (VBM) and regional volumetry were used to assess group comparisons and correlations between brain structural measurements as well as the duration and extent of hypoxia during GTCS. RESULTS: Morphometric and volumetric alterations appeared in association with peri-GTCS hypoxia, including volume loss in the periaqueductal gray (PAG), thalamus, hypothalamus, vermis, cerebellum, parabrachial pons, and medulla. Thalamic and PAG volume was significantly reduced in GTCS patients with severe hypoxia compared with GTCS patients with mild/moderate hypoxia. Brainstem volume loss appeared in both hypoxia groups, although it was more extensive in those with severe hypoxia. Significant negative partial correlations emerged between thalamic and hippocampal volume and extent of hypoxia, whereas vermis and accumbens volumes declined with increasing hypoxia duration. SIGNIFICANCE: Brain structural alterations in patients with GTCS are related to the extent of hypoxia in brain sites that serve vital functions. Although the changes are associative only, they provide evidence of injury to regulatory brain sites related to respiratory manifestations of seizures.

Volitional modulation of higher-order visual cortex alters human perception.

Can we change our perception by controlling our brain activation? Awareness during binocular rivalry is shaped by the alternating perception of different stimuli presented separately to each monocular view. We tested the possibility of causally influencing the likelihood of a stimulus entering awareness. To do this, participants were trained with neurofeedback, using realtime functional magnetic resonance imaging (rt-fMRI), to differentially modulate activation in stimulus-selective visual cortex representing each of the monocular images. Neurofeedback training led to altered bistable perception associated with activity changes in the trained regions. The degree to which training influenced perception predicted changes in grey and white matter volumes of these regions. Short-term intensive neurofeedback training therefore sculpted the dynamics of visual awareness, with associated plasticity in the human brain.

Guanidinoacetate methyltransferase (GAMT) deficiency: a rare but treatable epilepsy.

Epilepsy commonly presents in childhood as part of a syndrome, and some such children may reach adult services without an underlying syndromic diagnosis. For adult neurologists taking over their care, it is often unclear how hard to search for an underlying diagnosis. The diagnostic yield may be small and such a diagnosis may not change management. Young adults with learning difficulties are also challenging to investigate, as they may not tolerate standard epilepsy tests.We present such a case in which simple tests identified a unifying diagnosis. With the new diagnosis came a new treatment that had a significant impact on seizures and quality of life.

Relative valuation of pain in human orbitofrontal cortex.

The valuation of health-related states, including pain, is a critical issue in clinical practice, health economics, and pain neuroscience. Surprisingly the monetary value people associate with pain is highly context-dependent, with participants willing to pay more to avoid medium-level pain when presented in a context of low-intensity, rather than high-intensity, pain. Here, we ask whether context impacts upon the neural representation of pain itself, or alternatively the transformation of pain into valuation-driven behavior. While undergoing fMRI, human participants declared how much money they would be willing to pay to avoid repeated instances of painful cutaneous electrical stimuli delivered to the foot. We also implemented a contextual manipulation that involved presenting medium-level painful stimuli in blocks with either low- or high-level stimuli. We found no evidence of context-dependent activity within a conventional "pain matrix," where pain-evoked activity reflected absolute stimulus intensity. By contrast, in right lateral orbitofrontal cortex, a strong contextual dependency was evident, and here activity tracked the contextual rank of the pain. The findings are in keeping with an architecture where an absolute pain valuation system and a rank-dependent system interact to influence willing to pay to avoid pain, with context impacting value-based behavior high in a processing hierarchy. This segregated processing hints that distinct neural representations reflect sensory aspects of pain and components that are less directly nociceptive whose integration also guides pain-related actions. A dominance of the latter might account for puzzling phenomena seen in somatization disorders where perceived pain is a dominant driver of behavior.

Dopamine Regulates Approach-Avoidance in Human Sensation-Seeking.

BACKGROUND: Sensation-seeking is a trait that constitutes an important vulnerability factor for a variety of psychopathologies with high social cost. However, little is understood either about the mechanisms underlying motivation for intense sensory experiences or their neuropharmacological modulation in humans. METHODS: Here, we first evaluate a novel paradigm to investigate sensation-seeking in humans. This test probes the extent to which participants choose either to avoid or self-administer an intense tactile stimulus (mild electric stimulation) orthogonal to performance on a simple economic decision-making task. Next we investigate in a different set of participants whether this behavior is sensitive to manipulation of dopamine D2 receptors using a within-subjects, placebo-controlled, double-blind design. RESULTS: In both samples, individuals with higher self-reported sensation-seeking chose a greater proportion of mild electric stimulation-associated stimuli, even when this involved sacrifice of monetary gain. Computational modelling analysis determined that people who assigned an additional positive economic value to mild electric stimulation-associated stimuli exhibited speeding of responses when choosing these stimuli. In contrast, those who assigned a negative value exhibited slowed responses. These findings are consistent with involvement of low-level, approach-avoidance processes. Furthermore, the D2 antagonist haloperidol selectively decreased the additional economic value assigned to mild electric stimulation-associated stimuli in individuals who showed approach reactions to these stimuli under normal conditions (behavioral high-sensation seekers). CONCLUSIONS: These findings provide the first direct evidence of sensation-seeking behavior being driven by an approach-avoidance-like mechanism, modulated by dopamine, in humans. They provide a framework for investigation of psychopathologies for which extreme sensation-seeking constitutes a vulnerability factor.

Dread and the disvalue of future pain.

Standard theories of decision-making involving delayed outcomes predict that people should defer a punishment, whilst advancing a reward. In some cases, such as pain, people seem to prefer to expedite punishment, implying that its anticipation carries a cost, often conceptualized as 'dread'. Despite empirical support for the existence of dread, whether and how it depends on prospective delay is unknown. Furthermore, it is unclear whether dread represents a stable component of value, or is modulated by biases such as framing effects. Here, we examine choices made between different numbers of painful shocks to be delivered faithfully at different time points up to 15 minutes in the future, as well as choices between hypothetical painful dental appointments at time points of up to approximately eight months in the future, to test alternative models for how future pain is disvalued. We show that future pain initially becomes increasingly aversive with increasing delay, but does so at a decreasing rate. This is consistent with a value model in which moment-by-moment dread increases up to the time of expected pain, such that dread becomes equivalent to the discounted expectation of pain. For a minority of individuals pain has maximum negative value at intermediate delay, suggesting that the dread function may itself be prospectively discounted in time. Framing an outcome as relief reduces the overall preference to expedite pain, which can be parameterized by reducing the rate of the dread-discounting function. Our data support an account of disvaluation for primary punishments such as pain, which differs fundamentally from existing models applied to financial punishments, in which dread exerts a powerful but time-dependent influence over choice.

Investigating psychobiological causes and mechanisms in functional seizures and functional motor symptoms: Study protocol.

INTRODUCTION: Advances have been made in understanding the aetiology of functional neurological disorder (FND); however, its pathophysiological mechanisms have not been definitively demonstrated. Evidence suggests interacting roles for altered emotional processing and interoception, elevated autonomic arousal, and dissociation, but there is limited evidence demonstrating their causal influence on specific FND symptoms. Our superordinate aim is to elucidate potentially shared and distinct aetiological factors and mechanisms in two common FND subtypes, functional seizures (FS) and functional motor symptoms (FMS). METHODS: This study has a multimodal, mixed between- and within-groups design. The target sample is 50 individuals with FS, 50 with FMS, 50 clinical controls (anxiety/depression), and 50 healthy controls. Potential aetiological factors (e.g., adverse life events, physical/mental health symptoms, dissociative tendencies, interoceptive insight/sensibility) will be assessed with a detailed medical history interview and self-report questionnaires. A laboratory session will include a neurocognitive battery, psychophysiological testing, cardiac interoception and time estimation tasks and an isometric handgrip task. A subsample will undergo magnetic resonance imaging, including structural, resting-state and task-based scans combined with psychophysiological recording. Remote monitoring with ecological momentary assessment and wearables will measure variability in FND symptoms and their potential predictors/correlates for ≥2 weeks in patients' daily lives. Longitudinal follow-ups at 3, 6, and 12-months will monitor longer-term outcomes in the clinical groups. DISCUSSION: This study employs multimodal research methods to rigorously examine several putative mechanisms in FND, at subjective/experiential, behavioural, and physiological levels. The study will test causal hypotheses about the role of altered emotional processing, autonomic arousal, dissociation and interoception in the initiation or exacerbation of FND symptoms, directly comparing these processes in FS and FMS to healthy and clinical controls. This is the first study of its kind, with potential to reveal important targets for prevention and treatment of FND in future.

Limited clinical validity of univariate resting-state EEG markers for classifying seizure disorders.

Differentiating between epilepsy and psychogenic non-epileptic seizures presents a considerable challenge in clinical practice, resulting in frequent misdiagnosis, unnecessary treatment and long diagnostic delays. Quantitative markers extracted from resting-state EEG may reveal subtle neurophysiological differences that are diagnostically relevant. Two observational, retrospective diagnostic accuracy studies were performed to test the clinical validity of univariate resting-state EEG markers for the differential diagnosis of epilepsy and psychogenic non-epileptic seizures. Clinical EEG data were collected for 179 quasi-consecutive patients (age > 18) with a suspected diagnosis of epilepsy or psychogenic non-epileptic seizures who were medication-naïve at the time of EEG; 148 age- and gender-matched patients subsequently received a diagnosis from specialist clinicians and were included in the analyses. Study 1 is a hypothesis-driven study testing the ability of theta power and peak alpha frequency to classify people with epilepsy and people with psychogenic non-epileptic seizures, with an advanced machine learning pipeline. The next study (Study 2) is data-driven; a high number of quantitative EEG features are extracted and a similar machine learning approach as Study 1 assesses whether previously unexplored univariate EEG measures show promise as diagnostic markers. The results of Study 1 suggest that EEG markers that were previously identified as promising diagnostic indicators (i.e. theta power and peak alpha frequency) have limited clinical validity for the classification of epilepsy and psychogenic non-epileptic seizures (mean accuracy: 48%). The results of Study 2 indicate that identifying univariate markers that show good correlation with a categorical diagnostic label is challenging (mean accuracy: 45-60%). This is due to a considerable overlap in neurophysiological features between the diagnostic classes considered in this study, and to the presence of more dominant EEG dynamics such as alterations due to temporal proximity to epileptiform discharges. Markers that were identified in the context of previous epilepsy research using visually normal resting-state EEG were found to have limited clinical validity for the classification task of distinguishing between people with epilepsy and people with psychogenic non-epileptic seizures. A search for alternative diagnostic markers uncovered the challenges involved and generated recommendations for further research.

Interoception in functional motor symptoms and functional seizures: Preliminary evidence of intact accuracy alongside reduced insight and altered sensibility.

Altered interoception may be a pathophysiological mechanism in functional neurological disorder (FND). However, findings have been inconsistent across interoceptive dimensions in FND including functional motor symptoms (FMS) and seizures (FS). Here, individuals with FMS/FS (n = 17) and healthy controls (HC, n = 17) completed measures of interoceptive accuracy and insight (adapted heartbeat tracking task [HTT] with confidence ratings), a time estimation control task (TET) and the Multidimensional Assessment of Interoceptive Awareness-2 (MAIA-2) to assess interoceptive sensibility. The groups did not differ in interoceptive accuracy (p = 1.00, g = 0.00) or confidence (p = .99, g = 0.004), although the FMS/FS group displayed lower scores on the "Not-Distracting" (p < .001, g = 1.42) and "Trusting" (p = .005, g = 1.17) MAIA-2 subscales, relative to HCs. The groups did not differ in TET performance (p = .82, g = 0.08). There was a positive relationship between HTT accuracy and confidence (insight) in HCs (r = .61, p = .016) but not in FMS/FS (r = 0.11, p = .69). HTT confidence was positively correlated with MAIA-2 "Self-Regulation" (r = 0.77, p = .002) and negatively correlated with FND symptom severity (r = -0.84, p < .001) and impact (r = -0.86, p < .001) in FMS/FS. Impaired interoceptive accuracy may not be a core feature in FMS/FS, but reduced insight and altered sensibility may be relevant. Reduced certainty in self-evaluations of bodily experiences may contribute to the pathogenesis of FND symptoms.

Objective and subjective neurocognitive functioning in functional motor symptoms and functional seizures: preliminary findings.

INTRODUCTION: This study aimed to provide a preliminary assessment of objective and subjective neurocognitive functioning in individuals with functional motor symptoms (FMS) and/or functional seizures (FS). We tested the hypotheses that the FMS/FS group would display poorer objective attentional and executive functioning, altered social cognition, and reduced metacognitive accuracy. METHOD: Individuals with FMS/FS (n = 16) and healthy controls (HCs, n = 17) completed an abbreviated CANTAB battery, and measures of intellectual functioning, subjective cognitive complaints, performance validity, and comorbid symptoms. Subjective performance ratings were obtained to assess local metacognitive accuracy. RESULTS: The groups were comparable in age (p = 0.45), sex (p = 0.62), IQ (p = 0.57), and performance validity (p-values = 0.10-0.91). We observed no impairment on any CANTAB test in this FMS/FS sample compared to HCs, although the FMS/FS group displayed shorter reaction times on the Emotional Bias task (anger) (p = 0.01, np2 = 0.20). The groups did not differ in subjective performance ratings (p-values 0.15). Whilst CANTAB attentional set-shifting performance (total trials/errors) correlated with subjective performance ratings in HCs (p-values<0.005, rs = -0.85), these correlations were non-significant in the FMS/FS sample (p-values = 0.10-0.13, rs-values = -0.46-0.50). The FMS/FS group reported more daily cognitive complaints than HCs (p = 0.006, g = 0.92), which were associated with subjective performance ratings on CANTAB sustained attention (p = 0.001, rs = -0.74) and working memory tests (p < 0.001, rs = -0.75), and with depression (p = 0.003, rs = 0.70), and somatoform (p = 0.003, rs = 0.70) and psychological dissociation (p-values<0.005, rs-values = 0.67-0.85). CONCLUSIONS: These results suggest a discordance between objective and subjective neurocognitive functioning in this FMS/FS sample, reflecting intact test performance alongside poorer subjective cognitive functioning. Further investigation of neurocognitive functioning in FND subgroups is necessary.

Temporal Evolution of Multiday, Epileptic Functional Networks Prior to Seizure Occurrence.

Epilepsy is one of the most common neurological disorders, characterized by the occurrence of repeated seizures. Given that epilepsy is considered a network disorder, tools derived from network neuroscience may confer the valuable ability to quantify the properties of epileptic brain networks. In this study, we use well-established brain network metrics (i.e., mean strength, variance of strength, eigenvector centrality, betweenness centrality) to characterize the temporal evolution of epileptic functional networks over several days prior to seizure occurrence. We infer the networks using long-term electroencephalographic recordings from 12 people with epilepsy. We found that brain network metrics are variable across days and show a circadian periodicity. In addition, we found that in 9 out of 12 patients the distribution of the variance of strength in the day (or even two last days) prior to seizure occurrence is significantly different compared to the corresponding distributions on all previous days. Our results suggest that brain network metrics computed fromelectroencephalographic recordings could potentially be used to characterize brain network changes that occur prior to seizures, and ultimately contribute to seizure warning systems.

Distinct Patterns of Brain Metabolism in Patients at Risk of Sudden Unexpected Death in Epilepsy.

Objective: To characterize regional brain metabolic differences in patients at high risk of sudden unexpected death in epilepsy (SUDEP), using fluorine-18-fluorodeoxyglucose positron emission tomography (18FDG-PET). Methods: We studied patients with refractory focal epilepsy at high (n = 56) and low (n = 69) risk of SUDEP who underwent interictal 18FDG-PET as part of their pre-surgical evaluation. Binary SUDEP risk was ascertained by thresholding frequency of focal to bilateral tonic-clonic seizures (FBTCS). A whole brain analysis was employed to explore regional differences in interictal metabolic patterns. We contrasted these findings with regional brain metabolism more directly related to frequency of FBTCS. Results: Regions associated with cardiorespiratory and somatomotor regulation differed in interictal metabolism. In patients at relatively high risk of SUDEP, fluorodeoxyglucose (FDG) uptake was increased in the basal ganglia, ventral diencephalon, midbrain, pons, and deep cerebellar nuclei; uptake was decreased in the left planum temporale. These patterns were distinct from the effect of FBTCS frequency, where increasing frequency was associated with decreased uptake in bilateral medial superior frontal gyri, extending into the left dorsal anterior cingulate cortex. Significance: Regions critical to cardiorespiratory and somatomotor regulation and to recovery from vital challenges show altered interictal metabolic activity in patients with frequent FBTCS considered to be at relatively high-risk of SUDEP, and shed light on the processes that may predispose patients to SUDEP.

Dissociable codes of odor quality and odorant structure in human piriform cortex.

The relationship between odorant structure and odor quality has been a focus of olfactory research for 100 years, although no systematic correlations are yet apparent. Animal studies suggest that topographical representations of odorant structure in olfactory bulb form the perceptual basis of odor quality. Whether central olfactory regions are similarly organized is unclear. Using an olfactory version of fMRI cross-adaptation, we measured neural responses in primary olfactory (piriform) cortex as subjects smelled pairs of odorants systematically differing in quality and molecular functional group (as one critical attribute of odorant structure). Our results indicate a double dissociation in piriform cortex, whereby posterior regions encode quality (but not structure) and anterior regions encode structure (but not quality). The presence of structure-based codes suggests fidelity of sensory information arising from olfactory bulb. In turn, quality-based codes are independent of any simple structural configuration, implying that synthetic mechanisms may underlie our experience of smell.

Separate coding of different gaze directions in the superior temporal sulcus and inferior parietal lobule.

Electrophysiological recording in the anterior superior temporal sulcus (STS) of monkeys has demonstrated separate cell populations responsive to direct and averted gaze. Human functional imaging has demonstrated posterior STS activation in gaze processing, particularly in coding the intentions conveyed by gaze, but to date has provided no evidence of dissociable coding of different gaze directions. Because the spatial resolution typical of group-based fMRI studies (approximately 6-10 mm) exceeds the size of cellular patches sensitive to different facial characteristics (1-4 mm in monkeys), a more sensitive technique may be required. We therefore used fMRI adaptation, which is considered to offer superior resolution, to investigate whether the human anterior STS contains representations of different gaze directions, as suggested by non-human primate research. Subjects viewed probe faces gazing left, directly ahead, or right. Adapting to leftward gaze produced a reduction in BOLD response to left relative to right (and direct) gaze probes in the anterior STS and inferior parietal cortex; rightward gaze adaptation produced a corresponding reduction to right gaze probes. Consistent with these findings, averted gaze in the adapted direction was misidentified as direct. Our study provides the first human evidence of dissociable neural systems for left and right gaze.

Amygdala damage affects event-related potentials for fearful faces at specific time windows.

The amygdala is known to influence processing of threat-related stimuli in distant brain regions, including visual cortex. The time-course of these distant influences is unknown, although this information is important for resolving debates over likely pathways mediating an apparent rapidity in emotional processing. To address this, we recorded event-related potentials (ERPs) to seen fearful face expressions, in preoperative patients with medial temporal lobe epilepsy who had varying degrees of amygdala pathology, plus healthy volunteers. We found that amygdala damage diminished ERPs for fearful versus neutral faces within the P1 time-range, approximately 100-150 ms, and for a later component at approximately 500-600 ms. Individual severity of amygdala damage determined the magnitude of both these effects, consistent with a causal amygdala role. By contrast, amygdala damage did not affect explicit perception of fearful expressions nor a distinct emotional ERP effect at 150-250 ms. These results demonstrate two distinct time-points at which the amygdala influences fear processing. The data also demonstrate that while not all aspects of expression processing are disrupted by amygdala damage, there is a crucial impact on an early P1 component. These findings are consistent with the existence of multiple processing stages or routes for fearful faces that vary in their dependence on amygdala function.