Dr. Strangelove demystified: Disconnection of hand and language dominance explains alien-hand syndrome after corpus callosotomy.

BACKGROUND: Alien hand syndrome (AHS) is a disabling condition in which one hand behaves in a way that the person finds "alien". This feeling of alienation is related to the occurrence of movements of the respective hand performed without or against conscious intention. Most information on AHS stems from single case observations in patients with frontal, callosal, or parietal brain damage. METHODS: Retrospective analysis of distinctive clinical features of three out of 18 epilepsy patients who developed AHS with antagonistic movements of the left hand after corpus callosotomy (CC) (one anterior, two complete) for the control of epileptic seizures, particularly epileptic drop attacks (EDA). RESULTS: Remarkably, these three patients, two men and one woman, displayed atypical language dominance with a bilateral, left more than right hemisphere language representation in intracarotidal amobarbital testing before surgery. The overall additional distinctive feature of the target patients was genuine left-handedness, with writing retrained to right-handedness in two patients. After surgery the left hands became alien. The problem was permanent, despite strategies for compensation. CONCLUSION: From this observation we suggest that under the conditions of dissociation of language and motor dominance, loss of both intentional control of contralateral action and physiological inhibition of antagonistic movements lead to post-callosotomy alien-hand-like motor phenomena. The dissociation pattern posing this risk seems rare but needs to be considered when evaluating candidates for callosotomy.

Seizures associated with antibodies against cell surface antigens are acute symptomatic and not indicative of epilepsy: insights from long-term data.

BACKGROUND: Clinicians have questioned whether any disorder involving seizures and neural antibodies should be called "(auto)immune epilepsy." The concept of "acute symptomatic seizures" may be more applicable in cases with antibodies against neural cell surface antigens. We aimed at determining the probability of achieving seizure-freedom, the use of anti-seizure medication (ASM), and immunotherapy in patients with either constellation. As a potential pathophysiological correlate, we analyzed antibody titer courses. METHODS: Retrospective cohort study of 39 patients with seizures and neural antibodies, follow-up ≥ 3 years. RESULTS: Patients had surface antibodies against the N-methyl-D-aspartate receptor (NMDAR, n = 6), leucine-rich glioma inactivated protein 1 (LGI1, n = 11), contactin-associated protein-2 (CASPR2, n = 8), or antibodies against the intracellular antigens glutamic acid decarboxylase 65 kDa (GAD65, n = 13) or Ma2 (n = 1). Patients with surface antibodies reached first seizure-freedom (88% vs. 7%, P < 0.001) and terminal seizure-freedom (80% vs. 7%, P < 0.001) more frequently. The time to first and terminal seizure-freedom and the time to freedom from ASM were shorter in the surface antibody group (Kaplan-Meier curves: P < 0.0001 for first seizure-freedom; P < 0.0001 for terminal seizure-freedom; P = 0.0042 for terminal ASM-freedom). Maximum ASM defined daily doses were higher in the groups with intracellular antibodies. Seizure-freedom was achieved after additional immunotherapy, not always accompanied by increased ASM doses. Titers of surface antibodies but not intracellular antibodies decreased over time. CONCLUSION: Seizures with surface antibodies should mostly be considered acute symptomatic and transient and not indicative of epilepsy. This has consequences for ASM prescription and social restrictions. Antibody titers correlate with clinical courses.

Correction to: Routine diagnostics for neural antibodies, clinical correlates, treatment and functional outcome.

The original version of this article unfortunately contained a mistake.

Routine diagnostics for neural antibodies, clinical correlates, treatment and functional outcome.

OBJECTIVE: To determine frequencies, interlaboratory reproducibility, clinical ratings, and prognostic implications of neural antibodies in a routine laboratory setting in patients with suspected neuropsychiatric autoimmune conditions. METHODS: Earliest available samples from 10,919 patients were tested for a broad panel of neural antibodies. Sera that reacted with leucine-rich glioma-inactivated protein 1 (LGI1), contactin-associated protein-2 (CASPR2), or the voltage-gated potassium channel (VGKC) complex were retested for LGI1 and CASPR2 antibodies by another laboratory. Physicians in charge of patients with positive antibody results retrospectively reported on clinical, treatment, and outcome parameters. RESULTS: Positive results were obtained for 576 patients (5.3%). Median disease duration was 6 months (interquartile range 0.6-46 months). In most patients, antibodies were detected both in CSF and serum. However, in 16 (28%) patients with N-methyl-D-aspartate receptor (NMDAR) antibodies, this diagnosis could be made only in cerebrospinal fluid (CSF). The two laboratories agreed largely on LGI1 and CASPR2 antibody diagnoses (κ = 0.95). The clinicians (413 responses, 71.7%) rated two-thirds of the antibody-positive patients as autoimmune. Antibodies against the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), NMDAR (CSF or high serum titer), γ-aminobutyric acid-B receptor (GABABR), and LGI1 had ≥ 90% positive ratings, whereas antibodies against the glycine receptor, VGKC complex, or otherwise unspecified neuropil had ≤ 40% positive ratings. Of the patients with surface antibodies, 64% improved after ≥ 3 months, mostly with ≥ 1 immunotherapy intervention. CONCLUSIONS: This novel approach starting from routine diagnostics in a dedicated laboratory provides reliable and useful results with therapeutic implications. Counseling should consider clinical presentation, demographic features, and antibody titers of the individual patient.

Selective deep brain stimulation in the substantia nigra reduces myoclonus in progressive myoclonic epilepsy: a novel observation and short review of the literature.

We report the case of a patient suffering from pharmacotherapy-resistant bilateral progressive myoclonic epilepsy (PME) showing a beneficial response upon selective deep brain stimulation (DBS) of the substantia nigra pars reticulata. As an individual experimental therapeutic approach, we implanted DBS electrodes in the transitional zone between the subthalamic nucleus (STN) and the substantia nigra pars reticulata (SNr). Electrode placement allowed for a selective stimulation of either the STN, SNr, or both targets. Postoperatively, we observed a moderate subjective and objective improvement in positive and negative myoclonus by high-frequency DBS of the STN/SNr transitional zone. However, a systematic exploration of different stimulation settings revealed that monopolar stimulation of the substantia nigra alone was more effective than high-frequency monopolar DBS of either the motor STN (monopolar) or stimulation of both targets (STN/SNr). This observation confirms earlier findings showing that patients with PME benefit from high-frequency DBS. However, in contrast to previous reports stimulating the STN/SNr transitional zone, our patient showed the most significant effect upon selective stimulation of the SNr. We propose that in patients undergoing DBS for myoclonus, at least one electrode contact should be placed in the SNr allowing for selective monopolar stimulation of this target.

Right fronto-limbic atrophy is associated with reduced empathy in refractory unilateral mesial temporal lobe epilepsy.

Refractory mesial temporal lobe epilepsy (MTLE) is the most frequent focal epilepsy and is often accompanied by deficits in social cognition including emotion recognition, theory of mind, and empathy. Consistent with the neuronal networks that are crucial for normal social-cognitive processing, these impairments have been associated with functional changes in fronto-temporal regions. However, although atrophy in unilateral MTLE also affects regions of the temporal and frontal lobes that underlie social cognition, little is known about the structural correlates of social-cognitive deficits in refractory MTLE. In the present study, a psychometrically validated empathy questionnaire was combined with whole-brain voxel-based morphometry (VBM) to investigate the relationship between self-reported affective and cognitive empathy and gray matter volume in 55 subjects (13 patients with right MTLE, 9 patients with left MTLE, and 33 healthy controls). Consistent with the brain regions underlying social cognition, our results show that lower affective and cognitive empathy was associated with smaller volume in predominantly right fronto-limbic regions, including the right hippocampus, parahippocampal gyrus, thalamus, fusiform gyrus, inferior temporal gyrus, dorsomedial and dorsolateral prefrontal cortices, and in the bilateral midbrain. The only region that was associated with both affective and cognitive empathy was the right mesial temporal lobe. These findings indicate that patients with right MTLE are at increased risk for reduced empathy towards others' internal states and they shed new light on the structural correlates of impaired social cognition frequently accompanying refractory MTLE. In line with previous evidence from patients with neurodegenerative disease and stroke, the present study suggests that empathy depends upon the integrity of right fronto-limbic and brainstem regions and highlights the importance of the right mesial temporal lobe and midbrain structures for human empathy.

Right mesial temporal lobe epilepsy impairs empathy-related brain responses to dynamic fearful faces.

Unilateral mesial temporal lobe epilepsy (MTLE) has been associated with reduced amygdala responsiveness to fearful faces. However, the effect of unilateral MTLE on empathy-related brain responses in extra-amygdalar regions has not been investigated. Using functional magnetic resonance imaging, we measured empathy-related brain responses to dynamic fearful faces in 34 patients with unilateral MTLE (18 right sided), in an epilepsy (extra-MTLE; n = 16) and in a healthy control group (n = 30). The primary finding was that right MTLE (RMTLE) was associated with decreased activity predominantly in the right amygdala and also in bilateral periaqueductal gray (PAG) but normal activity in the right anterior insula. The results of the extra-MTLE group demonstrate that these reduced amygdala and PAG responses go beyond the attenuation caused by antiepileptic and antidepressant medication. These findings clearly indicate that RMTLE affects the function of mesial temporal and midbrain structures that mediate basic interoceptive input necessary for the emotional awareness of empathic experiences of fear. Together with the decreased empathic concern found in the RMTLE group, this study provides neurobehavioral evidence that patients with RMTLE are at increased risk for reduced empathy towards others' internal states and sheds new light on the nature of social-cognitive impairments frequently accompanying MTLE.

[Epilepsy And Driving Ability: The New Guideline]. / Epilepsie und Fahreignung: die neue Richtlinie.

The Swiss Guideline concerning epilepsy and driving has recently been revised. Recommendations have changed significantly in several respects. Some modifications arise indirectly from a change in the overall concept of epilepsy. As a consequence of the application of the new ILAE definition and diagnostic criteria for epilepsy, there are now cases in which the diagnosis of epilepsy is established even after one single seizure. Furthermore, a concept of imminent epilepsy was introduced to identify patients without seizures, but with a high risk of a first seizure within twelve months. On the other hand, the concept of a "resolved epilepsy" was established to loosen driving regulations for longterm seizure-free patients. In addition, the new guideline provides differential recommendations for provoked vs. unprovoked seizures in several clinical constellations.

Where's the action? The pragmatic turn in cognitive science.

In cognitive science, we are currently witnessing a 'pragmatic turn', away from the traditional representation-centered framework towards a paradigm that focuses on understanding cognition as 'enactive', as skillful activity that involves ongoing interaction with the external world. The key premise of this view is that cognition should not be understood as providing models of the world, but as subserving action and being grounded in sensorimotor coupling. Accordingly, cognitive processes and their underlying neural activity patterns should be studied primarily with respect to their role in action generation. We suggest that such an action-oriented paradigm is not only conceptually viable, but already supported by much experimental evidence. Numerous findings either overtly demonstrate the action-relatedness of cognition or can be re-interpreted in this new framework. We argue that new vistas on the functional relevance and the presumed 'representational' nature of neural processes are likely to emerge from this paradigm.

Alterations in functional connectivity of the amygdala in unilateral mesial temporal lobe epilepsy.

The aim of this work was to evaluate the relationship between ipsilateral amygdala dysfunction in unilateral mesial temporal lobe epilepsy (MTLE) and remote temporal, frontal, and parietal brain structures and to identify their association with theory of mind (ToM) abilities. Functional magnetic resonance imaging (fMRI) data were acquired from MTLE patients with unilateral hippocampal sclerosis (n = 28; 16 left-sided) and healthy controls (HC, n = 18) watching an animated fearful face paradigm. To explore functional connectivity, we used independent component analysis (ICA) of fMRI data to characterize possible amygdala network alterations that may be caused by lateralized amygdala dysfunction. We furthermore investigated the relationship between activation within the amygdala network and ToM task performance. The pattern of amygdalar BOLD activation observed in response to an animated fearful face paradigm was bilateral amygdalar activation in HC and amygdala activation lateralized to the contralateral side in MTLE patients. In HC, a hemispheric asymmetry of the amygdala network was present with amygdala co-activation in predominantly left temporolateral and frontal brain structures. In MTLE patients, the observed asymmetry of amygdala connectivity was modulated by the side of pathology and the extent of amygdalar connectivity to the parahippocampal gyrus and insula was related to ToM test performance. These findings suggest that ipsilateral amygdalar dysfunction in MTLE is associated with alterations in remote temporal and frontal brain areas. The study of psychiatric and neurological disorders via network analysis allows for a shift of focus away from viewing dysfunctions of individual structures to a pathological network that possibly gives rise to a variety of symptoms.

"Tell me how do I feel"--emotion recognition and theory of mind in symptomatic mesial temporal lobe epilepsy.

Specific interictal personality characteristics in epilepsy, sometimes referred to as "Waxman-Geschwind Syndrome", have been recognized for centuries and extensively described. Despite the persevering clinical impression that patients with mesial temporal lobe epilepsies (MTLE) suffer from problems in communication and interpersonal relations, uncertainties and controversies remain as to the precise origin of these psychosocial difficulties. Here, we investigated social-cognitive and decision-making abilities using a set of tasks that combine behavioural and psychological measures of social and emotional variables to answer the question of whether patients with MTLE are specifically impaired in social cognition compared to both an epilepsy and a healthy control group. MTLE patients, an epilepsy control group (extra-MTLE; patients with epilepsy, not originating within the frontal or mesial temporal lobe) and healthy controls (HC) were assessed according to their general cognitive status as well as with our Social Cognition Battery, which included tests of basic processes of social cognition, theory of mind, decision making, and various aspects of psychopathology and quality of life. MTLE patients were significantly impaired compared to HC on most measures of the Social Cognition Battery. MTLE patients were predominantly impaired in general emotion recognition compared to extra-MTLE patients. Performance in the epilepsy control group, although not significantly differing from performance in either the MTLE or the healthy control group, lay between these two groups. MTLE can be considered a significant risk factor for the development of deficits in social cognition beyond weaknesses that might be associated with epilepsy as a stigmatized chronic neurological disorder. The presence of deficits in social cognition may explain various behavioural symptoms that have historically driven concepts such as "epileptic personality" or "interictal personality disorder" and may indicate new routes for therapeutic interventions.

Hippocampal contributions to the processing of architectural ranking.

Theories of rhetoric and architecture suggest that buildings designed to be high ranking according to the Western architectural decorum have more impact on the minds of their beholders than low-ranking buildings. Here, we used event-related potentials in a visual object categorization task to probe this assumption and to examine whether the hippocampus contributes to the processing of architectural ranking. We found that early negative potentials between 200 and 400 ms differentiated between high- and low-ranking buildings in healthy subjects and patients with temporal lobe epilepsy with and without hippocampal sclerosis. By contrast, late positive potentials between 400 and 600 ms were higher in amplitude to high-ranking buildings only in healthy subjects and TLE patients without but not in TLE patients with hippocampal sclerosis. These findings suggest that the differentiation between high- and low-ranking buildings entails both early visual object selection and late post-model selection processes and that the hippocampus proper contributes critically to this second stage of visual object categorization.

Brain electrical responses to high- and low-ranking buildings.

Since the ancient world, architecture generally distinguishes two categories of buildings with either high- or low-ranking design. High-ranking buildings are supposed to be more prominent and, therefore, more memorable. Here, we recorded event-related potentials (ERPs) to drawings of buildings with either high- or low-ranking architectural ornaments and found that ERP responses between 300 and 600 ms after stimulus presentation recorded over both frontal lobes were significantly more positive in amplitude to high-ranking buildings. Thus, ERPs differentiated reliably between both classes of architectural stimuli although subjects were not aware of the two categories. We take our data to suggest that neurophysiological correlates of building perception reflect aspects of an architectural rule system that adjust the appropriateness of style and content ("decorum"). Since this rule system is ubiquitous in Western architecture, it may define architectural prototypes that can elicit familiarity memory processes.

Attention effects on sensory gating--intracranial and scalp recordings.

The function of sensory gating is usually studied in paired-click experiments and quantified by the decrease of the event-related potential (ERP) component P50 and other ERP components from the 1st to the 2nd stimuli. The impact of attention on these gating measures is still not fully resolved. In the current study, the impact of attention on sensory gating was studied by scalp and intracranial recordings. The study sample consisted of epilepsy and tumor patients undergoing presurgical evaluation by means of implanted electrodes. In the unattend condition, patients had no overt task. In the active condition, patients had to count simultaneously trials with paired clicks, as well as interspersed trials with single clicks. The ERPs in the active condition were characterized by an underlying negativity both for scalp and neocortical recordings, reaching their maximum at the N100 latency of the 2nd stimulus. A time-frequency analysis revealed that this attention effect comprised only low frequency signals (<3 Hz). In line with that, P50 amplitude and P50 gating were unaffected by attention when data were filtered from 10 to 50 Hz. In addition, attention effects were revealed for intrahippocampal ERP components and for induced high frequency neocortical gamma band activity. Findings indicate that N100 and P200 gating measures can potentially be affected by attention and have to be interpreted carefully when studying clinical populations.

Intracranially recorded memory-related potentials reveal higher posterior than anterior hippocampal involvement in verbal encoding and retrieval.

The human hippocampus is essential for both encoding and recollection, but it remains controversial whether there is a functionally different involvement of anterior versus posterior parts of the hippocampus in these memory processes. In the present study, we examined encoding and retrieval processes via intrahippocampal recordings in 27 patients with unilateral temporal lobe epilepsy. Multicontact depth electrodes were implanted along the longitudinal axis of the hippocampus as part of the presurgical evaluation. In a continuous word recognition test, subjects had to indicate whether words were new or already presented. Recognized old words, as compared to new words, resulted in a larger P600 component, as well as in a larger late negative component (LNC, 600-900 msec). In addition, subsequently remembered words elicited a larger positivity (400 to 900 msec) than later forgotten words. We found differences concerning the distribution along the hippocampus for the LNC old-new effect, reflecting successful retrieval, as well as for the subsequent memory effect, reflecting successful encoding. Both effects were larger the further posterior an electrode was located in the hippocampus. Findings are suggestive for a predominant posterior hippocampal involvement in both verbal encoding and retrieval.

Limbic event-related potentials to words and pictures in the presurgical evaluation of temporal lobe epilepsy.

We recorded limbic event-related potentials (ERPs) with intrahippocampal depth electrodes in a more demanding verbal and an easier pictorial continuous recognition task in patients undergoing presurgical evaluations of their medical refractory mesial temporal lobe epilepsies (MTLE). In all cases depth electrodes were implanted because non-invasive studies could not demonstrate unilateral seizure-onset unequivocally. For the present study we only considered 24 patients who eventually were found to suffer from unilateral MTLE, in whom hippocampal sclerosis (HS) was confirmed histologically, and who were seizure-free post-operatively. We found that the rhinal anterior medial temporal lobe N400 (AMTL-N400) to first presentations of words but not to pictures was reduced in amplitude on the side of seizure origin. Our data suggest that limbic ERPs to words are more sensitive to the epileptogenic process than those to pictures. Thus, if limbic ERPs are recorded as part of invasive presurgical evaluations, verbal instead of pictorial recognition paradigms should be employed.

Gender specific processing of eye contact within the human medial temporal lobe.

Eye contact is a powerful social stimulus for human and non-human primates. However, it is unclear whether brain mechanisms that interpret eye contact are sensitive to gender. Here we show that human brain responses to eye contact are indeed gender specific. Recording event-related potentials directly from the medial temporal lobes, we found that eye contact elicited specific responses in men only when they saw female faces. Conversely, women responded specifically to eye contact only when they saw pictures of men. Thus, the human medial temporal lobes subserve specifically the processing of eye contact with persons of the opposite gender.

Hippocampal event-related potentials to tone duration deviance in a passive oddball paradigm in humans.

The mismatch negativity (MMN), a component of event-related potentials (ERPs), is assumed to reflect a preattentive auditory discrimination process. Although an involvement of hippocampal structures in deviance detection was shown in animal experiments, invasive recordings in humans have not been able to provide such an evidence so far. In the current study, ERPs were recorded from intrahippocampal and scalp electrodes in 16 epilepsy patients. Stimulation consisted of trains of six tones, with one tone deviating in duration (100 vs. 50 ms). In the rhinal cortex, ERPs elicited by deviants were larger in amplitude than those of standards (around 200 ms). The rhinal activation was succeeded by a long-lasting hippocampal ERP component (around 350 ms). However, in contrast to the rhinal activation, hippocampal activation was also elicited by the 1st stimuli of the train and might, therefore, be related more to salience detection than to deviance detection. The current study provides evidence that the MMN is part of a multistage comparison process and that the rhinal cortex is part of its underlying cortical network.