The (In)flexible self: Psychopathology, mindfulness, and neuroscience

Clinical and neuroscientific evidence indicates that transdiagnostic processes contribute to the generation and maintenance of psychopathological symptoms and disorders. Rigidity (inflexibility) appears a core feature of most transdiagnostic pathological processes. Decreasing rigidity may prove important to restore and maintain mental health. One of the primary domains in which rigidity and flexibility plays a role concerns the self. We adopt the pattern theory of self (PTS) for a working definition of self. This incorporates the pluralist view on self as constituted by multiple aspects or processes, understood to constitute a self-pattern, i.e. processes organized in non-linear dynamical relations across a number of time scales. The use of mindfulness meditation in the format of Mindfulness Based Interventions (MBIs) has been developed over four decades in Clinical Psychology. MBIs are promising as evidence-based treatments, shown to be equivalent to gold-standard treatments and superior to specific active controls in several randomized controlled trials. Notably, MBIs have been shown to target transdiagnostic symptoms. Given the hypothesized central role of rigid, habitual self-patterns in psychopathology, PTS offers a useful frame to understand how mindfulness may be beneficial in decreasing inflexibility. We discuss the evidence that mindfulness can alter the psychological and behavioral expression of individual aspects of the self-pattern, as well as favour change in the self-pattern as a whole gestalt. We discuss neuroscientific research on how the phenomenology of the self (pattern) is reflected in associated cortical networks and meditation-related alterations in cortical networks. Creating a synergy between these two aspects can increase understanding of psychopathological processes and improve diagnostic and therapeutic options. (AU)

The (In)flexible self: Psychopathology, mindfulness, and neuroscience.

Clinical and neuroscientific evidence indicates that transdiagnostic processes contribute to the generation and maintenance of psychopathological symptoms and disorders. Rigidity (inflexibility) appears a core feature of most transdiagnostic pathological processes. Decreasing rigidity may prove important to restore and maintain mental health. One of the primary domains in which rigidity and flexibility plays a role concerns the self. We adopt the pattern theory of self (PTS) for a working definition of self. This incorporates the pluralist view on self as constituted by multiple aspects or processes, understood to constitute a self-pattern, i.e. processes organized in non-linear dynamical relations across a number of time scales. The use of mindfulness meditation in the format of Mindfulness Based Interventions (MBIs) has been developed over four decades in Clinical Psychology. MBIs are promising as evidence-based treatments, shown to be equivalent to gold-standard treatments and superior to specific active controls in several randomized controlled trials. Notably, MBIs have been shown to target transdiagnostic symptoms. Given the hypothesized central role of rigid, habitual self-patterns in psychopathology, PTS offers a useful frame to understand how mindfulness may be beneficial in decreasing inflexibility. We discuss the evidence that mindfulness can alter the psychological and behavioral expression of individual aspects of the self-pattern, as well as favour change in the self-pattern as a whole gestalt. We discuss neuroscientific research on how the phenomenology of the self (pattern) is reflected in associated cortical networks and meditation-related alterations in cortical networks. Creating a synergy between these two aspects can increase understanding of psychopathological processes and improve diagnostic and therapeutic options.

Seizures as a Struggle between Life and Death: An Existential Approach to the Psychosocial Impact of Seizures in Candidates for Epilepsy Surgery.

INTRODUCTION: Mental health comorbidities such as depression and anxiety are common in epilepsy, especially among people with pharmacoresistant epilepsy who are candidates for epilepsy surgery. The Psychology Task Force of the International League Against Epilepsy advised that psychological interventions should be integrated into comprehensive epilepsy care. METHODS: To better understand the psychological impact of epilepsy and epileptic seizures in epilepsy surgery candidates, we analysed interviews with this subgroup of patients using Karl Jaspers' concept of limit situations, which are characterised by a confrontation with the limits and challenges of life. These are especially chance, randomness, and unpredictability, death and finitude of life, struggle and self-assertion, guilt, failure, and falling short of one's aspirations. RESULTS: In 43 interviews conducted with 15 people with drug-resistant epilepsy who were candidates for epilepsy surgery, we found that these themes are recurrent and have a large psychosocial impact, which can result in depression and anxiety. For some people, epileptic seizures appear to meet the criteria for traumatic events. CONCLUSION: Understanding epilepsy and seizures as existential challenges complements the neurobiological explanations for psychological comorbidities and can help tailor psychological interventions to the specific needs of people with epilepsy, especially those who are candidates for surgical treatment.

TMS-evoked EEG potentials demonstrate altered cortical excitability in migraine with aura.

Migraine is associated with altered sensory processing, that may be evident as changes in cortical responsivity due to altered excitability, especially in migraine with aura. Cortical excitability can be directly assessed by combining transcranial magnetic stimulation with electroencephalography (TMS-EEG). We measured TMS evoked potential (TEP) amplitude and response consistency as these measures have been linked to cortical excitability but were not yet reported in migraine.We recorded 64-channel EEG during single-pulse TMS on the vertex interictally in 10 people with migraine with aura and 10 healthy controls matched for age, sex and resting motor threshold. On average 160 pulses around resting motor threshold were delivered through a circular coil in clockwise and counterclockwise direction. Trial-averaged TEP responses, frequency spectra and phase clustering (over the entire scalp as well as in frontal, central and occipital midline electrode clusters) were compared between groups, including comparison to sham-stimulation evoked responses.Migraine and control groups had a similar distribution of TEP waveforms over the scalp. In migraine with aura, TEP responses showed reduced amplitude around the frontal and occipital N100 peaks. For the migraine and control groups, responses over the scalp were affected by current direction for the primary motor cortex, somatosensory cortex and sensory association areas, but not for frontal, central or occipital midline clusters.This study provides evidence of altered TEP responses in-between attacks in migraine with aura. Decreased TEP responses around the N100 peak may be indicative of reduced cortical GABA-mediated inhibition and expand observations on enhanced cortical excitability from earlier migraine studies using more indirect measurements.

A neurophenomenological approach to non-ordinary states of consciousness: hypnosis, meditation, and psychedelics.

No contemporary unifying framework has been provided for the study of non-ordinary states of consciousness (NSCs) despite increased interest in hypnosis, meditation, and psychedelics. NSCs induce shifts in experiential contents (what appears to the experiencer) and/or structure (how it appears). This can allow the investigation of the plastic and dynamic nature of experience from a multiscale perspective that includes mind, brain, body, and context. We propose a neurophenomenological (NP) approach to the study of NSCs which highlights their role as catalysts of transformation in clinical practice by refining our understanding of the relationships between experiential (subjective) and neural dynamics. We outline the ethical implications of the NP approach for standard conceptions of health and pathology as well as the crucial role of experience-based know-how in NSC-related research and application.

"What is this strange sensation?" A qualitative exploration of metaphors used to verbalise hard-to-describe experiences by people with epilepsy.

Mental health comorbidities are frequent in epilepsy. Consequently, psychotherapy is becoming increasingly important. To address the psychological needs of people with epilepsy (PwE) it is essential to understand the subjective experiences of seizures better. There is little research on how people report seizures, and which psychological representations they have. We conducted a thematic analysis based on 42 (micro-phenomenological) interviews with 15 participants on their experiences of seizures. In these interviews, we identified three categories of seizure descriptions: (1) phenomena related to the body and emotions; (2) the moments that are difficult to describe; and (3) the use of figurative language and metaphors. Paroxysmal physical and psychological sensations were often reported spontaneously by the participants. The moments that were difficult to describe were expressed, among other things, through the use of paradoxes or the report of a 'strange' feeling and led participants to use figurative language. As these metaphors can reveal important information about people's subjective experiences, they were analyzed in detail. We identified the three main types of metaphors that the participants used most frequently: (1) perception, (2) nature, and (3) battle. The theme of battle was most frequently used in different forms and was closely related to the metaphors from the fields of perception and nature, thus representing a key point in the personal experience of seizures. These findings can contribute to developing psychotherapeutic approaches for the treatment of seizure disorders.

Tracking cortical excitability dynamics with transcranial magnetic stimulation in focal epilepsy.

INTRODUCTION: The lack of reliable biomarkers constrain epilepsy management. We assessed the potential of repeated transcranial magnetic stimulation with electromyography (TMS-EMG) to track dynamical changes in cortical excitability on a within-subject basis. METHODS: We recruited people with refractory focal epilepsy who underwent video-EEG monitoring and drug tapering as part of the presurgical evaluation. We performed daily TMS-EMG measurements with additional postictal assessments 1-6 h following seizures to assess resting motor threshold (rMT), and motor evoked potentials (MEPs) with single- and paired-pulse protocols. Anti-seizure medication (ASM) regimens were recorded for the day before each measurement and expressed in proportion to the dosage before tapering. Additional measurements were performed in healthy controls to evaluate day-to-day rMT variability. RESULTS: We performed 77 (58 baseline, 19 postictal) measurements in 16 people with focal epilepsy and 35 in seven healthy controls. Controls showed minimal day-to-day rMT variation. Withdrawal of ASMs was associated with a lower rMT without affecting MEPs of single- and paired-pulse TMS-EMG paradigms. Postictal measurements following focal to bilateral tonic-clonic seizures demonstrated unaltered rMT and increased short interval intracortical inhibition, while measurements following focal seizures with impaired awareness showed decreased rMT's and reduced short and long interval intracortical inhibition. CONCLUSION: Serial within-subject rMT measurements yielded reproducible, stable results in healthy controls. ASM tapering and seizures had distinct effects on TMS-EMG excitability indices in people with epilepsy. Drug tapering decreased rMT, indicating increased overall corticospinal excitability, whereas seizures affected intracortical inhibition with contrasting effects between seizure types.

Neural dynamics of mindfulness meditation and hypnosis explored with intracranial EEG: A feasibility study.

PURPOSE: Intracranial electroencephalography (iEEG) offers a unique window on brain dynamics with excellent temporal and spatial resolution and is less prone to recording artefacts than surface EEG. This study used a within-subject design to explore the feasibility to compare iEEG data during mind wandering, mindfulness meditation and hypnosis. RESULTS: Three patients who had iEEG for clinical monitoring and who were new to mindfulness meditation and hypnosis were able to enter these states. We found non-specific and wide-spread amplitude modulations. Data-driven connectivity analysis revealed widespread connectivity patterns that were common across the three conditions. These were predominant in the low frequencies (delta, theta and alpha) and characterised by positively correlated activity. Connectivity patterns that were unique to the three conditions predominated in the gamma band, one third of the correlations in these patterns were negative. CONCLUSIONS: This study is the first to support the feasibility of a direct comparison of the neural correlates of mindfulness meditation and hypnosis using iEEG. These modulations may reflect the complex interplay between different known brain networks, and warrant further functional investigations in particular in the gamma band.

Headache in people with epilepsy.

Epidemiological estimates indicate that individuals with epilepsy are more likely to experience headaches, including migraine, than individuals without epilepsy. Headaches can be temporally unrelated to seizures, or can occur before, during or after an episode; seizures and migraine attacks are mostly not temporally linked. The pathophysiological links between headaches (including migraine) and epilepsy are complex and have not yet been fully elucidated. Correct diagnoses and appropriate treatment of headaches in individuals with epilepsy is essential, as headaches can contribute substantially to disease burden. Here, we review the insights that have been made into the associations between headache and epilepsy over the past 5 years, including information on the pathophysiological mechanisms and genetic variants that link the two disorders. We also discuss the current best practice for the management of headaches co-occurring with epilepsy and highlight future challenges for this area of research.

Incidence and Prevalence of Drug-Resistant Epilepsy: A Systematic Review and Meta-analysis.

OBJECTIVE: To evaluate the incidence and prevalence of drug-resistant epilepsy (DRE) as well as its predictors and correlates, we conducted a systematic review and meta-analysis of observational studies. METHODS: Our protocol was registered with PROSPERO, and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and Meta-analysis of Observational Studies in Epidemiology reporting standards were followed. We searched MEDLINE, Embase, and Web of Science. We used a double arcsine transformation and random-effects models to perform our meta-analyses. We performed random-effects meta-regressions using study-level data. RESULTS: Our search strategy identified 10,794 abstracts. Of these, 103 articles met our eligibility criteria. There was high interstudy heterogeneity and risk of bias. The cumulative incidence of DRE was 25.0% (95% confidence interval [CI]: 16.8-34.3) in child studies but 14.6% (95% CI: 8.8-21.6) in adult/mixed age studies. The prevalence of DRE was 13.7% (95% CI: 9.2-19.0) in population/community-based populations but 36.3% (95% CI: 30.4-42.4) in clinic-based cohorts. Meta-regression confirmed that the prevalence of DRE was higher in clinic-based populations and in focal epilepsy. Multiple predictors and correlates of DRE were identified. The most reported of these were having a neurologic deficit, an abnormal EEG, and symptomatic epilepsy. The most reported genetic predictors of DRE were polymorphisms of the ABCB1 gene. CONCLUSIONS: Our observations provide a basis for estimating the incidence and prevalence of DRE, which vary between populations. We identified numerous putative DRE predictors and correlates. These findings are important to plan epilepsy services, including epilepsy surgery, a crucial treatment option for people with disabling seizures and DRE.

BLAST paradigm: A new test to assess brief attentional fluctuations in children with epilepsy, ADHD, and normally developing children.

BACKGROUND: Pure attentional deficits are still underdiagnosed in children with epilepsy. While attention-deficit hyperactivity disorder (ADHD) is historically the most studied cause of attentional disorders, an important number of children with epilepsy and attentional complaints do not fully meet the DSM-V (Diagnostic and Statistical Manual of Mental Disorders - Fifth Edition) criteria for ADHD and may be excluded from specific care. Clinical tools currently available are insufficient to detect more subtle but clinically relevant attentional fluctuations. OBJECTIVE/METHODS: The recently developed Bron-Lyon Attention Stability Test (BLAST) was used to evaluate brief attentional fluctuations with a high temporal precision. Drawing on two new attentional indices, we evaluated spontaneous fluctuations of response accuracy and timing, underlying attentional stability. The main objective was to assess attentional stability in children with i) epilepsy with comorbid ADHD, ii) epilepsy without comorbid ADHD, iii) ADHD not medicated and without epilepsy, and iv) normal development. Further objectives were to assess the main determinants of attentional stability in those groups, including the effect of factors related to the epileptic condition. RESULTS: In 122 children with epilepsy (67 with comorbid ADHD), 52 children with ADHD, and 53 healthy controls, we demonstrated lower attentional stability in both the groups with epilepsy and ADHD compared with healthy children. In children with epilepsy, BLAST scores were negatively associated with earlier seizure onset and AED (antiepileptic drug) polytherapy, while the seizure frequency, epilepsy duration, or type did not influence BLAST scores. CONCLUSIONS: This study demonstrates that attentional stability is impaired in children with epilepsy and/or ADHD. Bron-Lyon Attention Stability Test seems to be a sensitive test to detect attentional stability deficit in children with epilepsy and with attentional complaints who did not meet all criteria of ADHD. We propose that BLAST could be a useful clinical neuropsychological tool to assess attentional disorders in children.

The Use of Caffeine by People with Epilepsy: the Myths and the Evidence.

PURPOSE OF REVIEW: Caffeine is the most widely consumed central nervous stimulant. For people with epilepsy, it is often unclear whether drinking coffee carries a risk of triggering seizures. RECENT FINDINGS: The relationship between caffeine, seizures, epilepsy, and anti-seizure drugs is not fully understood. Clinical studies are scarce. In animal models, caffeine can increase seizure susceptibility but can also protect from seizures. Effects seem dose-dependent and are influenced by the duration of intake and the developmental stage at which caffeine exposure started. Caffeine reduces the efficacy of several anti-seizure medications, especially topiramate. It is unclear how these findings, mainly from animal studies, can be translated to the clinical condition. At present, there is no evidence to advise people with epilepsy against the use or overuse of caffeine. Until clinical studies suggest otherwise, caffeine intake should be considered as a factor in achieving and maintaining seizure control in epilepsy.

Phase clustering in transcranial magnetic stimulation-evoked EEG responses in genetic generalized epilepsy and migraine.

BACKGROUND: Epilepsy and migraine are paroxysmal neurological conditions associated with disturbances of cortical excitability. No useful biomarkers to monitor disease activity in these conditions are available. Phase clustering was previously described in electroencephalographic (EEG) responses to photic stimulation and may be a potential epilepsy biomarker. OBJECTIVE: The objective of this study was to investigate EEG phase clustering in response to transcranial magnetic stimulation (TMS), compare it with photic stimulation in controls, and explore its potential as a biomarker of genetic generalized epilepsy or migraine with aura. METHODS: People with (possible) juvenile myoclonic epilepsy (JME), migraine with aura, and healthy controls underwent single-pulse TMS with concomitant EEG recording during the interictal period. We compared phase clustering after TMS with photic stimulation across the groups using permutation-based testing. RESULTS: We included eight people with (possible) JME (five off medication, three on), 10 with migraine with aura, and 37 controls. The TMS and photic phase clustering spectra showed significant differences between those with epilepsy without medication and controls. Two phase clustering-based indices successfully captured these differences between groups. One participant was tested multiple times. In this case, the phase clustering-based indices were inversely correlated with the dose of antiepileptic medication. Phase clustering did not differ between people with migraine and controls. CONCLUSION: We present methods to quantify phase clustering using TMS-EEG and show its potential value as a measure of brain network activity in genetic generalized epilepsy. Our results suggest that the higher propensity to phase clustering is not shared between genetic generalized epilepsy and migraine.

Differentiating motor phenomena in tilt-induced syncope and convulsive seizures.

OBJECTIVE: We assessed motor phenomena in syncope and convulsive seizures to aid differential diagnosis and understand the pathophysiologic correlates. METHODS: We studied video-EEG recordings of tilt-induced syncope and convulsive seizures in participants aged 15 years and older. Syncope was defined as (1) loss of consciousness (video-assessed), (2) circulatory changes (accelerating blood pressure decrease with or without bradycardia/asystole), and (3) EEG changes ("slow" or "slow-flat-slow"). We assessed myoclonic jerks and tonic postures of the arms and noted time of occurrence, laterality, synchrony, and rhythmicity (mean consecutive differences of interclonic intervals). RESULTS: Video-EEG records of 65 syncope cases and 50 convulsive seizures were included. In syncope, postures occurred in 42 cases (65%) and jerks in 33 (51%). Fewer jerks occurred in syncope (median 2, range 1-19) compared to convulsive seizures (median 48, range 20-191; p < 0.001). Jerks were more rhythmic in seizures compared to syncope (p < 0.001). Atonia was seen in all syncope cases, while this was not observed in any seizure. Jerks predominantly occurred during the slow and postures during the flat EEG phase. CONCLUSIONS: Jerks and tonic postures were common in syncope, but semiology differed from convulsive seizures. The lack of overlap in the number of jerks suggests that less than 10 indicates syncope and more than 20 a convulsive seizure: the "10/20 rule." Loss of tone strongly favors syncope. The EEG correlates imply that jerks in syncope are likely of cortical origin, whereas tonic postures may result from brainstem disinhibition.

Caffeine and seizures: A systematic review and quantitative analysis.

PURPOSE: Caffeine is the most commonly used central nervous system (CNS) stimulant. The relationship between caffeine, seizures, epilepsy, and antiepileptic drugs (AEDs) is complex and not fully understood. Case reports suggest that caffeine triggers seizures in susceptible people. Our systematic review reports on the relationship between caffeine, seizures, and drugs in animal and human studies. Quantitative analyses were also done on animal studies regarding the effects of caffeine on AEDs. METHODS: PubMed was searched for studies assessing the effects of caffeine on seizure susceptibility, epilepsy, and drug interactions in people and in animal models. To quantify the interaction between AEDs and caffeine, the data of six animal studies were pooled and analyzed using a general linear model univariate analysis or One-way Analysis of Variance (ANOVA). RESULTS: In total, 442 items were identified from which we included 105 studies. Caffeine can increase seizure susceptibility and protect from seizures, depending on the dose, administration type (chronic or acute), and the developmental stage at which caffeine exposure started. In animal studies, caffeine decreased the antiepileptic potency of some drugs; this effect was strongest in topiramate. CONCLUSION: Preclinical studies suggest that caffeine increases seizure susceptibility. In some cases, chronic use of caffeine may protect against seizures. Caffeine lowers the efficacy of several drugs, especially topiramate. It is unclear how these findings in models can be translated to the clinical condition. Until clinical studies suggest otherwise, caffeine intake should be considered as a factor in achieving and maintaining seizure control in epilepsy.

Long-interval intracortical inhibition as biomarker for epilepsy: a transcranial magnetic stimulation study.

Cortical excitability, as measured by transcranial magnetic stimulation combined with electromyography, is a potential biomarker for the diagnosis and follow-up of epilepsy. We report on long-interval intracortical inhibition data measured in four different centres in healthy controls (n = 95), subjects with refractory genetic generalized epilepsy (n = 40) and with refractory focal epilepsy (n = 69). Long-interval intracortical inhibition was measured by applying two supra-threshold stimuli with an interstimulus interval of 50, 100, 150, 200 and 250 ms and calculating the ratio between the response to the second (test stimulus) and to the first (conditioning stimulus). In all subjects, the median response ratio showed inhibition at all interstimulus intervals. Using a mixed linear-effects model, we compared the long-interval intracortical inhibition response ratios between the different subject types. We conducted two analyses; one including data from the four centres and one excluding data from Centre 2, as the methods in this centre differed from the others. In the first analysis, we found no differences in long-interval intracortical inhibition between the different subject types. In all subjects, the response ratios at interstimulus intervals 100 and 150 ms showed significantly more inhibition than the response ratios at 50, 200 and 250 ms. Our second analysis showed a significant interaction between interstimulus interval and subject type (P = 0.0003). Post hoc testing showed significant differences between controls and refractory focal epilepsy at interstimulus intervals of 100 ms (P = 0.02) and 200 ms (P = 0.04). There were no significant differences between controls and refractory generalized epilepsy groups or between the refractory generalized and focal epilepsy groups. Our results do not support the body of previous work that suggests that long-interval intracortical inhibition is significantly reduced in refractory focal and genetic generalized epilepsy. Results from the second analysis are even in sharper contrast with previous work, showing inhibition in refractory focal epilepsy at 200 ms instead of facilitation previously reported. Methodological differences, especially shorter intervals between the pulse pairs, may have contributed to our inability to reproduce previous findings. Based on our results, we suggest that long-interval intracortical inhibition as measured by transcranial magnetic stimulation and electromyography is unlikely to have clinical use as a biomarker of epilepsy.