The relevance of neuropsychiatric symptoms and cognitive problems in new-onset epilepsy - Current knowledge and understanding.

Neurobehavioral and cognition problems are highly prevalent in epilepsy, but most research studies to date have not adequately addressed the precise nature of the relationship between these comorbidities and seizures. To address this complex issue and to facilitate collaborative, innovative research in the rising field of neurobehavioral comorbidities and cognition disturbances in new-onset epilepsy, international epilepsy experts met at the 3rd Halifax International Epilepsy Conference & Retreat at White Point, South Shore, Nova Scotia, Canada from September 18 to 20, 2014. This Conference Proceedings provides a summary of the conference proceedings. Specifically, the following topics are discussed: (i) role of comorbidities in epilepsy diagnosis and management, (ii) role of antiepileptic medications in understanding the relationship between epilepsy and neurobehavioral and cognition problems, and (iii) animal data and diagnostic approaches. Evidence to date, though limited, strongly suggests a bidirectional relationship between epilepsy and cognitive and psychiatric comorbidities. In fact, it is likely that seizures and neurobehavioral problems represent different symptoms of a common etiology or network-wide disturbance. As a reflection of this shared network, psychiatric comorbidities and/or cognition problems may actually precede the seizure occurrence and likely get often missed if not screened.

Touching and feeling: differences in pleasant touch processing between glabrous and hairy skin in humans.

Previous functional magnetic resonance imaging studies in two rare patients, together with microneurography and psychophysical observations in healthy subjects, have demonstrated a system of mechanosensitive C-fiber tactile (CT) afferents sensitive to slowly moving stimuli. They project to the posterior insular cortex and signal pleasant aspects of touch. Importantly, CTs have not been found in the glabrous skin of the hand, yet it is commonly observed that glabrous skin touch is also perceived as pleasant. Here we asked if the brain processing of pleasant touch differs between hairy and glabrous skin by stroking the forearm and glabrous skin of the hand during positron emission tomography. The data showed that, when contrasting slow brush stroking on the forearm with slow brush stroking on the palm, there were significant activations of the posterior insular cortex and mid-anterior orbitofrontal cortex. The opposite contrast showed a significant activation of the somatosensory cortices. Although concurrent psychophysical ratings showed no differences in intensity or pleasantness ratings, a subsequent touch questionnaire in which subjects used a newly developed 'touch perception task' showed significant difference for the two body sites. Emotional descriptors received higher ratings on the forearm and sensory descriptors were rated more highly on the palm. The present findings are consistent with the hypothesis that pleasant touch from hairy skin, mediated by CT afferents, is processed in the limbic-related cortex and represents an innate non-learned process. In contrast, pleasant touch from glabrous skin, mediated by A-beta afferents, is processed in the somatosensory cortex and represents an analytical process dependent on previous tactile experiences.

Sex differences in the medial temporal lobe during encoding and recognition of pseudowords and abstract designs.

Sex differences in various cognitive abilities have been demonstrated in terms of performance differentials and, more recently, in differences in activation patterns during fMRI. Hemispheric lateralization is sometimes accentuated in sex differences; e.g., women demonstrating greater activation of the left hemisphere than men during verbal tasks. We were interested in whether this phenomenon applies to memory for words and designs (i.e., material specific memory). Using analogous verbal (pseudowords) and nonverbal (abstract designs) encoding and recognition tasks completed back-to-back in a 3T scanner, we found that women tend to show exaggerated left hippocampal activation during certain stages of encoding and recognition of verbal information, compared with men. Likewise (although to a lesser extent), men showed more right hippocampal activation than women did during the abstract design learning task. These results have important implications for the generalization of fMRI memory study results, for example to clinical populations such as patients undergoing epilepsy surgery.

Intracarotid amobarbital procedure and etomidate speech and memory test.

The intracarotid amobarbital procedure (IAP) has for over 50 years been an important component of the presurgical investigation of patients with epilepsy who are candidates for surgical intervention as treatment for their seizures. Owing to increasing frequency and duration of amobarbital shortages, alternatives for this drug have been sought and implemented, but until now only the drug was changed, while the basic procedure remained essentially the same as that used with amobarbital. This paper describes the Montreal Neurological Institute experience using etomidate in place of amobarbital and introducing a significant change in the procedure: after an initial bolus injection, an infusion is used to maintain the level of hemianesthesia during critical test times. Results of 28 patients tested with this procedure are compared to results from 40 patients tested in the standard IAP.

Memory and the medial temporal lobe: hemispheric specialization reconsidered.

The role of the medial temporal lobe in learning and memory has been well established in research on humans and other animals. In humans, clinical and neuroimaging studies typically suggest material-specific lateralization in which the left and right temporal lobes are associated with verbal and nonverbal memory, respectively. It is often assumed that the temporal lobes are functionally alike, differing only in terms of the content to be learned. Here we present data that challenge this notion, showing that the type of material used during a memory task can influence fMRI activation patterns beyond the expected left-verbal/right-nonverbal dichotomy. Our results also suggest some degree of functional asymmetry in the medial temporal lobe that is independent of material type, pointing to underlying processing differences between the left and right temporal lobes.

Etomidate speech and memory test (eSAM): a new drug and improved intracarotid procedure.

BACKGROUND: The intracarotid amobarbital procedure (IAP) is an important part of comprehensive investigation of patients who are candidates for surgical treatment of epilepsy. Owing to repeated and lengthy shortages of amobarbital, causing delays in elective surgery, attempts have been made to find a suitable alternative anesthetic. The authors report their experience using etomidate, a widely used agent for the induction of anesthesia. METHODS: Sixteen consecutive patients requiring IAP to evaluate memory or to lateralize speech underwent the procedure using etomidate. Prior to the procedure a catheter was placed in the internal carotid artery and an angiogram was performed. EEG was recorded and read online by an electroencephalographer. An anesthetist injected the drug, administered by bolus followed by an infusion, which was maintained until each speech measure had been sampled and new memory items had been introduced. The infusion was then stopped and testing continued as in a standard IAP. RESULTS: In all cases (30 hemispheres) contralateral hemiplegia followed injection. EEG slow waves were observed in every injected hemisphere, with some contralateral slowing anteriorly in 18. Global aphasia with preserved attention and cooperation followed dominant-hemisphere injections. These phenomena remained during infusion, and upon its termination returned gradually to baseline over a period of about 4 minutes. CONCLUSIONS: Etomidate is a viable alternative to amobarbital, and its administration by bolus followed by infusion offers an improvement over the traditional intracarotid amobarbital procedure. Cognitive tests can be performed during an assured hemianesthesia of the injected hemisphere.

Functional neuroimaging of odor imagery.

We used positron emission tomography (PET) to investigate brain regions associated with odor imagery. Changes in regional cerebral blood flow (CBF) during odor imagery were compared with changes during nonspecific expectation of olfactory stimuli and with those during odor perception. Sixty-seven healthy volunteers were screened for their odor imagery (with a paradigm developed in a previous study), and 12 of them, assessed to be "good odor imagers," participated in the neuroimaging part of the study. Imagination of odors was associated with increased activation in several olfactory regions in the brain: the left primary olfactory cortical (POC) region including piriform cortex, the left secondary olfactory cortex or posterior orbitofrontal cortex (OFC), and the rostral insula bilaterally. Furthermore, blood flow in two regions within the right orbitofrontal cortex correlated significantly with the behavioral measure of odor imagery during scanning. Overall, the findings indicated that neural networks engaged during odor perception and imagery overlap partially.

Gustatory agnosia.

OBJECTIVE: To report the assessment of a patient exhibiting gustatory agnosia. METHODS: Preoperative and postoperative neuropsychological, neuroimaging, and chemosensory evaluations were performed in a 39-year-old woman undergoing surgical treatment for intractable epilepsy. RESULTS: Preoperative MRIs showed bilateral (right > left) atrophy in the medial temporal lobes and complete atrophy of the left insula. Evaluation of gustatory function revealed normal suprathreshold intensity estimation, affective evaluation, and detection thresholds but elevated recognition thresholds. A functional neuroimaging study showed activation to stimulation of aversive taste in the left amygdala. Surgical treatment entailed resection from the left medial temporal lobe that included the region of amygdala that had responded to taste. Postoperatively, detection, naming, and intensity estimation for taste remained normal, but the patient was unable to recognize different tastes (sweet, sour, salty, and bitter). A second evaluation 2.5 years after her surgery revealed no change in taste ability. CONCLUSION: The anteromedial temporal lobe has an important role in recognizing taste quality.

Odor-induced changes in taste perception.

We investigated odor-induced changes in taste perception (OICTP), by examining the influence of strawberry and soy sauce odors on perceived sweetness (Experiment 1) and saltiness (Experiment 2). We explored whether taste-smell interactions occur at the central level, by delivering odorants (strawberry, soy sauce, odorless water) and tastants (sucrose, sodium chloride) separately, and whether effects of imagined odors are comparable to those of physically presented odors. We found specific taste-smell interactions: sweetness enhancement induced by strawberry odor and saltiness enhancement induced by soy sauce odor. These interactions were elicited with separate delivery of olfactory and gustatory stimuli. Secondly, we found a similar but rather limited effect with the imagined odors: imagined strawberry enhanced perceived sweetness of water solutions, and imagined soy sauce enhanced perceived saltiness of weak sodium chloride solutions. We concluded that OICTP is a centrally mediated phenomenon, and that imagined odors can to some extent induce changes in perceived taste intensity comparable to those elicited by perceived odors.

Effects of perceived and imagined odors on taste detection.

We assessed the influence of different odors on detection of a sweet tastant, and the ability of imagined odors to elicit the same effects as perceived odors on taste perception. The tastant used was sucrose, and the two odorants were strawberry and ham. In the first experiment, participants either smelled or imagined one of two odors during taste detection tasks (between-subject design), whereas in the second one, subjects completed both the odor imagery and perception conditions with taste detection tasks (within-subject design). The effect was odorant-specific: detection of sucrose was significantly better when subjects smelled strawberry than when they smelled ham. Furthermore, imagined odors influenced taste perception in the same way as did perceived odors. We concluded that the odor-specific effect on taste perception is an authentic perceptual phenomenon. Our results also support the notion that odor-induced changes in taste perception are mediated centrally. Finally, our findings are in agreement with reports supporting the existence of odor imagery.

The mind's nose: Effects of odor and visual imagery on odor detection.

We examined odor imagery by looking for its effects on detection of weak odors. Seventy-two healthy subjects performed a forced-choice odor detection task in one of three conditions: after being told to imagine an odor (odor imagery), after being told to imagine an object (visual imagery), or without having received imagery instructions (no-imagery control). For the two imagery conditions, the presented and imagined stimuli were either the same (matched) or different (mismatched). There was a significant difference between detection in the matched and mismatched conditions for odor imagery, but not for visual imagery. We conclude that our paradigm does measure odor imagery and that the effect of imagery on detection is both content- and modality-specific. Further, the difference between conditions was due to lower detection with mismatched odor imagery than without imagery, indicating that interference underlies the effect.

Working memory in another dimension: functional imaging of human olfactory working memory.

The majority of working memory research has been carried out within the visual and auditory modalities, leaving it unclear how other modalities would map onto currently proposed working memory models. In this study we examined the previously uninvestigated area of olfactory working memory. Our aim was to investigate if olfactory working memory would engage prefrontal regions known to be involved in working memory for other sensory modalities. Using positron emission tomography we measured cerebral blood flow changes in 12 volunteers during an olfactory working memory task and a comparison visual working memory task. Our findings indicate that both olfactory and face working memory engaged dorsolateral and ventrolateral frontal cortex when the task requirements were matched; a conjunction analysis indicated overlap in the distribution of activity in the two tasks. Similarities and differences in activity were noted in parietal lobe regions, with both tasks engaging inferior areas of 40/7, but only visual working memory showing increased activity within left superior parietal cortex. The findings support the idea that working memory processes engage frontal cortical areas independent of the modality of input, but do not rule out the possibility of modality-specific neural populations within dorsolateral or ventrolateral cortex.

Changes in brain activity related to eating chocolate: from pleasure to aversion.

We performed successive H(2)(15)O-PET scans on volunteers as they ate chocolate to beyond satiety. Thus, the sensory stimulus and act (eating) were held constant while the reward value of the chocolate and motivation of the subject to eat were manipulated by feeding. Non-specific effects of satiety (such as feelings of fullness and autonomic changes) were also present and probably contributed to the modulation of brain activity. After eating each piece of chocolate, subjects gave ratings of how pleasant/unpleasant the chocolate was and of how much they did or did not want another piece of chocolate. Regional cerebral blood flow was then regressed against subjects' ratings. Different groups of structures were recruited selectively depending on whether subjects were eating chocolate when they were highly motivated to eat and rated the chocolate as very pleasant [subcallosal region, caudomedial orbitofrontal cortex (OFC), insula/operculum, striatum and midbrain] or whether they ate chocolate despite being satiated (parahippocampal gyrus, caudolateral OFC and prefrontal regions). As predicted, modulation was observed in cortical chemosensory areas, including the insula and caudomedial and caudolateral OFC, suggesting that the reward value of food is represented here. Of particular interest, the medial and lateral caudal OFC showed opposite patterns of activity. This pattern of activity indicates that there may be a functional segregation of the neural representation of reward and punishment within this region. The only brain region that was active during both positive and negative compared with neutral conditions was the posterior cingulate cortex. Therefore, these results support the hypothesis that there are two separate motivational systems: one orchestrating approach and another avoidance behaviours.

Increased intensity perception of aversive taste following right anteromedial temporal lobe removal in humans.

We used a modified version of the Spatial Taste Test to assess taste intensity perception in patients with either left or right temporal resection from the anteromedial temporal lobe (AMTL), and a group of control subjects. Sweet, sour, salty and bitter solutions were applied onto discrete locations of the tongue to stimulate either left or right fungiform, or left or right foliate papillae. Intensity ratings were assessed with the Labeled Magnitude Scale. Subjects also sipped 5 ml of each solution for whole mouth stimulation. Genetically based determinants of taste sensitivity were assessed with ratings of 6-n-propylthiouracil, and covaried from all analyses. As in previous studies, analysis of covariance indicated that the subjects in the right temporal group rated an aversive bitter taste as more intense than did subjects in the control group. In contrast, there were no group differences for sucrose ratings, suggesting that the AMTL may be involved preferentially in processing aversive compared with hedonic tastes. No group x side, or group x location effects were present. These results confirm that removal of the right AMTL in humans results in increased taste intensity/aversiveness perception. This finding complements existing literature indicating that the AMTL is important for processing aversive taste, and suggests that inhibitory mechanisms may play an important role in such processing.

Changes in taste intensity perception following anterior temporal lobe removal in humans.

To investigate the role of the anterior temporal lobe in taste perception, we compared taste intensity estimations made by patients who had removal from either the left or the right anterior temporal lobe for the treatment of intractable epilepsy with a group of healthy control subjects. Estimations were made for five concentrations of each of four different tastes, as well as for five cards of varying saturations of gray, which served as a control task. A cross-modal magnitude estimation procedure was employed in which subjects used distance on a measuring tape to reflect intensity estimation. Distances were then transformed into logs, and the slope and the correlation with stimulus concentration or saturation was calculated. Correlation was taken as a measure of accuracy of estimation and slope was taken as a measure of perceived intensity. As predicted, repeated measures analysis of variance (ANOVA) revealed a significant difference between the control group and both patient groups in taste intensity estimations, but not for grayness, reflecting the importance of the anterior temporal lobe in low-level gustatory but not visual perception. Additionally, repeated measures ANOVA for slopes indicated that subjects in the right temporal group rated the bitter taste as more intense than did subjects in other groups, possibly reflecting increased intensity perception of the unpleasant bitter taste.

Face learning and memory: the twins test.

The clinical utility of current face recognition tests has been questioned. To evaluate if a new paradigm may measure this type of memory more accurately, the authors created a novel test to examine face learning (previously uninvestigated) and short- and long-term retention. For this initial investigation of test sensitivity to hemisphere of dysfunction, patients with surgical resection from a temporal lobe and healthy subjects were tested. Recognition was evaluated on 3 trials: after a single exposure, after 4 exposures (for learning), and after a 24-hr delay interval. Patients with a right resection performed significantly worse than healthy controls and patients with left resection. There was no difference between patients with a left resection and controls. Classification of individual patients to side of resection based on test results showed higher sensitivity (82%) than published for other tests and maintained good specificity (79%).

Neural mechanisms involved in odor pleasantness and intensity judgments.

Olfactory processing in the human brain was examined using positron emission tomography. Twelve normal volunteers were scanned while smelling pairs of odors: they were asked to judge which odor was more pleasant in one condition, and which was more intense in a second condition; they also were scanned while sniffing an odorless stimulus. As in prior studies, greater cerebral blood flow was found in the right orbitofrontal cortex during both pleasantness and intensity judgments as compared to baseline. Cerebellar activity was also seen, but contrary to expectations no activity was detected in the primary olfactory (piriform) cortex. Only the pleasantness judgment elicited additional activity within the hypothalamus, suggesting that this structure may be involved in affective processing that requires access to information about internal state.

Neuropsychological assessment for temporal lobe epilepsy surgery.

Neuropsychological assessment consists of a comprehensive evaluation of cognitive functioning and most often some evaluation of motor skills and sensory status also. Cognitive functions sampled typically include "intelligence" (IQ tests), attention, language skills, visuospatial abilities, "executive skills" and other abilities associated with frontal-lobe function, and learning and memory. Thus, the assessment samples vary widely among a variety of functions, providing a comprehensive picture of an individual's strengths and weaknesses. The resulting pattern points to the probable site of epileptic focus. Neuropsychological findings also serve to predict the risk for postsurgical cognitive decline and, when performance before and after operation is compared, they provide data on the impact of surgery upon cognitive functioning. Comprehensive evaluation of learning and memory is particularly important in this context, because of the frequency of temporal lobe epilepsy and the prominence of memory dysfunction associated with it. In addition, patients slated for elective surgery may also undergo an intracarotid amobarbital procedure (IAP), which is performed to determine the side of cerebral dominance for language and to test the memory capabilities of each hemisphere alone. All of these specialized neuropsychological tools are discussed in this paper.