Donald L. Schomer

Reproductive endocrine disorders in women with partial seizures of temporal lobe origin

Of 50 consecutive women with partial seizures of temporal lobe origin (temporal lobe epilepsy [TLE]) evaluated for reproductive dysfunction, 28 had menstrual problems. Of those, 19 had reproductive endocrine disorders. Polycystic ovarian syndrome and hypogonadotropic hypogonadism occurred significantly more often in women with TLE than in the general female population. Polycystic ovarian syndrome was associated with predominantly left-sided lateralization of interictal epileptic discharges; hypogonadotropic hypogonadism was more commonly found with right-sided discharges. Hyposexuality occurred more often in women with predominantly right-sided interictal epileptic discharges and was associated with low serum luteinizing hormone levels. There are several possible interpretations: epileptic discharges in medial temporal limbic structures may disrupt hypothalamic regulation of pituitary gonadotropin secretion; anovulatory cycles of reproductive endocrine disorders may promote the development of epileptic discharges; and TLE and some associated reproductive endocrine disorders may represent the parallel effects of prenatal factors common to the development of the brain and the reproductive system.

Monitoring the patient's EEG during echo planar MRI

The recording of an EEG while the patient is undergoing magnetic resonance imaging (MRI) data acquisition, as far as we are aware, has not been previously accomplished. By careful selection and arrangement of analog multiplexed cable-telemetry equipment to eliminate both ferrous and RF sources, a stable, readable EEG can be obtained without interfering with the diagnostic quality of the MRI. This arrangement does not cause localized heating or burning at the electrode sites. This technical capability permits more accurate neurophysiological control during the acquisition of echo planar functional MRI studies as well as providing indications of anatomical localization of electrical sources.

Sequential Processing of Lexical, Grammatical, and Phonological Information Within Broca’s Area

Seeing the Brains One, Two, Three Taking advantage of the rare opportunity to record neuronal activity in the human brain using intracranial electrodes, Sahin et al. (p. 445; see the Perspective by Hagoort and Levelt) document the spatial and temporal pattern of neuronal populations within Brocas area as patients thought of a single word, changed its tense (for verbs) or number (for nouns), and articulated the word silently. For these three stages, they detected activity at 200, 320, and 450 milliseconds, moving in a caudal to rostral direction. These data fit neatly within the roughly 600 milliseconds required for the onset of speech and map the distinct neural computations within an area of the brain, known for almost a century and a half, as important for the production of language. Intracranial electrodes record activity in a language-associated area of the brain as words are identified and produced. Words, grammar, and phonology are linguistically distinct, yet their neural substrates are difficult to distinguish in macroscopic brain regions. We investigated whether they can be separated in time and space at the circuit level using intracranial electrophysiology (ICE), namely by recording local field potentials from populations of neurons using electrodes implanted in language-related brain regions while people read words verbatim or grammatically inflected them (present/past or singular/plural). Neighboring probes within Broca’s area revealed distinct neuronal activity for lexical (~200 milliseconds), grammatical (~320 milliseconds), and phonological (~450 milliseconds) processing, identically for nouns and verbs, in a region activated in the same patients and task in functional magnetic resonance imaging. This suggests that a linguistic processing sequence predicted on computational grounds is implemented in the brain in fine-grained spatiotemporally patterned activity.TRCs, with taste at the periphery proposed to be encoded via labeled lines [i.e., a sweet line, a sour line, a bitter line, etc. (21)]. Given that Car4 is specifically tethered to the surface of sour-sensing cells, and thus ideally poised to provide a highly localized acid signal to the sour TRCs, we reasoned that carbonation might be sensed through activation of the sour-labeled line. A prediction of this postulate is that prevention of sour cell activation should eliminate CO2 detection, even in the presence of wild-type Car4 function. To test this hypothesis, we engineered animals in which the activation of nerve fibers innervating sour-sensing cells was blocked by preventing neurotransmitter release from the PKD2L1-expressing TRCs. In essence, we transgenically targeted expression of tetanus toxin light chain [TeNT, an endopeptidase that removes an essential component of the synaptic machinery (34–36)] to sour-sensing TRCs, and then monitored the physiological responses of these mice to sweet, sour, bitter, salty, umami and CO2 stimulation. As predicted, taste responses to sour stimuli were selectively and completely abolished, whereas responses to sweet, bitter, salty and umami tastants remained unaltered (Fig. 4 and fig. S5). However, these animals also displayed a complete loss of taste responses to CO2 even though they still expressed Car4 on the surface of PKD2L1 cells. Together, these results implicate the extracellular generation of protons, rather than intracellular acidification (15), as the primary signal that mediates the taste of CO2, and demonstrate that sour cells not only provide the membrane anchor for Car4 but also serve as the cellular sensors for carbonation. Why do animals need CO2 sensing? CO2 detection could have evolved as a mechanism to recognize CO2-producing sources (18, 37)—for instance, to avoid fermenting foods. This view would be consistent with the recent discovery of a specialized CO2 taste detection in insects where it mediates robust innate taste behaviors (38). Alternatively, Car4 may be important to maintain the pH balance within taste buds, and might gratuitously function as a detector for carbonation only as an accidental consequence. Although CO2 activates the sour-sensing cells, it does not simply taste sour to humans. CO2 (like acid) acts not only on the taste system but also in other orosensory pathways, including robust stimulation of the somatosensory system (17, 22); thus, the final percept of carbonation is likely to be a combination of multiple sensory inputs. Nonetheless, the “fizz” and “tingle” of heavily carbonated water is often likened to mild acid stimulation of the tongue, and in some cultures seltzer is even named for its salient sour taste (e.g., saurer Sprudel or Sauerwasser).

Sleep‐inducing effects of low doses of melatonin ingested in the evening

We previously observed that low oral doses of melatonin given at noon increase blood melatonin concentrations to those normally occurring nocturnally and facilitate sleep onset, as assessed using an involuntary muscle relaxation test. In this study we examined the induction of polysomnographically recorded sleep by similar doses given later in the evening, close to the times of endogenous melatonin release and habitual sleep onset. Volunteers received the hormone (oral doses of 0.3 or 1.0 mg) or placebo at 6, 8, or 9 PM. Latencies to sleep onset, to stage 2 sleep, and to rapid eye movement (REM) sleep were measured polysomnographically. Either dose given at any of the three time points decreased sleep onset latency and latency to stage 2 sleep. Melatonin did not suppress REM sleep or delay its onset. Most volunteers could clearly distinguish between the effects of melatonin and those of placebo when the hormone was tested at 6 or 8 PM. Neither melatonin dose induced “hangover” effects, as assessed with mood and performance tests administered on the morning after treatment. These data provide new evidence that nocturnal melatonin secretion may be involved in physiologic sleep onset and that exogenous melatonin may be useful in treating insomnia.

EEG-triggered echo-planar functional MRI in epilepsy

We investigated whether: (1) EEG recordings could be successfully performed in an MRI imager, (2) subclinical epileptic discharges could be used to trigger ultrafast functional MRI images, (3) artifact-free functional MRI images could be obtained while the patient was having the EEG monitored, and (4) the functional MRI images so obtained would show focal signal increases in relation to epileptic discharges. We report our results in two patients who showed focally higher signal intensity, reflective of increased local blood flow, in ultrafast functional MRI timed to epileptic discharges recorded while the patients were in the imager and compared with images not associated with discharges. One patient showed a focal increase despite a clinical and EEG history of generalized discharges. This approach may have the potential to identify brain regions activated during brief focal epileptic discharges. NEUROLOGY 1996;47: 89-93

Responses of Human Anterior Cingulate Cortex Microdomains to Error Detection, Conflict Monitoring, Stimulus-Response Mapping, Familiarity, and Orienting

Human anterior cingulate cortex (ACC) activity modulation has been observed in numerous tasks, consistent with a wide variety of functions. However, previous recordings have not had sufficient spatial resolution to determine whether microdomains (approximately one to two columns) are involved in multiple tasks, how activity is distributed across cortical layers, or indeed whether modulation reflected neuronal excitation, inhibition, or both. In this study, linear arrays of 24 microelectrodes were used to estimate population synaptic currents and neuronal firing in different layers of ACC during simple/choice reaction time, delayed word recognition, rhyming, auditory oddball, and cued conditional letter-discrimination tasks. Responses to all tasks, with differential responses to errors, familiarity, difficulty, and orienting, were recorded in single microdomains. The strongest responses occurred ∼300-800 ms after stimulus onset and were usually a current source with inhibited firing, strongly suggesting active inhibition in superficial layers during the behavioral response period. This was usually followed by a sink from ∼800 to 1400 ms, consistent with postresponse rebound activation. Transient phase locking of task-related theta activity in superficial cingulate layers suggested extended interactions with medial and lateral frontal and temporal sites. These data suggest that each anterior cingulate microdomain participates in a multilobar cortical network after behavioral responses in a variety of tasks.

Evidence for rapid face recognition from human scalp and intracranial electrodes

It is still generally believed that complex visual analysis is not carried out within the first 100 ms. Here we show that intra-and extracranial visual evoked potentials (VEPs) differentiate previously seen faces from novel faces as early as 50 ms after stimulus onset. EEG was recorded from scalp electrodes in 12 male healthy volunteers (group I) and intracranially from implanted depth electrodes in the temporal and frontal cortex of seven epilepsy patients (group II). Both groups were engaged in a face recognition task. All subjects showed significant differential responses which occurred very early (50–90 ms) and later (190–600 ms). In group II, the early responses were recorded more frequently in the right hemisphere, whereas the late differential VEPs were found in both hemispheres. Both types of VEPs were more frequent in the temporal neocortex, underlining its role as a major contributor to these fast recognition processes.

The association of stigma with self-management and perceptions of health care among adults with epilepsy

OBJECTIVE The purpose of this study was to examine the perception of stigma among adults with epilepsy including its association with epilepsy self-management and perceptions of health care. METHODS Participants for the study were recruited from two epilepsy centers and a neurology clinic. Individuals agreeing to participate in the study were asked to complete three assessments each 3 months apart. Data were collected from 320 adult men and women with epilepsy; 314 provided responses on stigma and were included in this analysis. RESULTS Participants ranged in age from 19 to 75 years (mean=43). Fifty percent of the sample was female, and 80% was white. The mean age of seizure onset was 22 years, and 76% of participants reported having had a seizure within the past year. Analysis suggests levels of perceived stigma are similar for men and women and across ethnic and age groups. However, participants who were not married or living with a partner, were not working for pay, and had limited income reported higher levels of stigma than did married participants, those working for pay, and those in higher income brackets. Participants reporting higher levels of stigma included those who had their first seizure before the age of 50 and a seizure in the last year. Participants whose seizures interfered more with activities, who rated their seizures as under less control, and who were not legally able to drive also reported higher levels of stigma. Tests of association between stigma and health-related variables revealed that participants reporting higher levels of perceived stigma also reported lower levels of self-efficacy to manage epilepsy; more negative outcome expectancies related to treatment and seizures; and lower levels of medication management, medication adherence, and patient satisfaction. However, they also reported greater management of information related to seizures. In regression analysis, income, age at first seizure, seizures during the past year, lower self-efficacy, negative outcome expectancies for seizures, and less patient satisfaction explained 54% of the variance in perceived stigma. CONCLUSIONS The results of the study suggest that perceived stigma is significant for people with epilepsy and is associated with factors that are known to be important in the management of epilepsy. Understanding who is at greatest risk for feeling stigmatized could lead to the development of preventive measures.

Differential effects of antiepileptic drugs on sexual function and hormones in men with epilepsy

Objective: To compare sexual function and reproductive hormone levels among men with epilepsy who took various antiepileptic drugs (AEDs), untreated men with epilepsy, and normal controls. Methods: Subjects were 85 men with localization-related epilepsy (25 on carbamazepine [CBZ], 25 on phenytoin [PHT], 25 on lamotrigine [LTG], and 10 untreated for at least 6 months [no AED]) and 25 controls. Sexual function scores (S-scores), hormone levels (bioactive testosterone, estradiol), hormone ratios (bioactive testosterone/bioactive estradiol), and gonadal efficiency (bioactive testosterone/luteinizing hormone) were compared among the five groups. Results: S-scores, bioactive testosterone levels, bioactive testosterone/bioactive estradiol, and bioactive testosterone/luteinizing hormone were significantly greater in the control and LTG groups than in the CBZ and PHT groups. Sex hormone binding globulin was significantly higher in the CBZ and PHT groups than in all other groups. S-scores were below the control range in 20% of the men with epilepsy, including 32.0% on CBZ, 24% on PHT, 20% on no AEDs, and 4% on LTG (χ2: p = 0.08 for all four groups; χ2: p = 0.02 for the three AED groups). Bioactive testosterone was below the control range in 28.2%, including 48% on CBZ, 28% on PHT, 20% on no AEDs, and 12% on LTG (χ2: p = 0.02). Among men with epilepsy who had low S-scores, 70.6% had bioactive testosterone levels below the control range as compared to 17.6% among men with normal S-scores (χ2: p < 0.0001). Among men with epilepsy who had abnormally low bioactive testosterone, 50.0% had low S-scores; among men with normal bioactive testosterone, 8.2% had low S-scores (χ2: p < 0.0001). Bioactive testosterone decline with age was significantly greater among men with epilepsy than among controls and notably greater in the CBZ and PHT groups than in the LTG and untreated groups. Conclusions: Sexual function, bioavailable testosterone levels, and gonadal efficiency in men with epilepsy who took lamotrigine were comparable to control and untreated values and significantly greater than with carbamazepine or phenytoin treatment.

The value of multichannel MEG and EEG in the presurgical evaluation of 70 epilepsy patients

OBJECTIVE To evaluate the sensitivity of a simultaneous whole-head 306-channel magnetoencephalography (MEG)/70-electrode EEG recording to detect interictal epileptiform activity (IED) in a prospective, consecutive cohort of patients with medically refractory epilepsy that were considered candidates for epilepsy surgery. METHODS Seventy patients were prospectively evaluated by simultaneously recorded MEG/EEG. All patients were surgical candidates or were considered for invasive EEG monitoring and had undergone an extensive presurgical evaluation at a tertiary epilepsy center. MEG and EEG raw traces were analysed individually by two independent reviewers. RESULTS MEG data could not be evaluated due to excessive magnetic artefacts in three patients (4%). In the remaining 67 patients, the overall sensitivity to detect IED was 72% (48/67 patients) for MEG and 61% for EEG (41/67 patients) analysing the raw data. In 13% (9/67 patients), MEG-only IED were recorded, whereas in 3% (2/67 patients) EEG-only IED were recorded. The combined sensitivity was 75% (50/67 patients). CONCLUSION Three hundred and six-channel MEG has a similarly high sensitivity to record IED as EEG and appears to be complementary. In one-third of the EEG-negative patients, MEG can be expected to record IED, especially in the case of lateral neocortical epilepsy and/or cortical dysplasia.