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.

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.

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.

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.

Intracranial EEG study of brain structures affected by internal carotid injection of amobarbital.

Hippocampal function, considered critical in memory processing, is supposedly tested in the intracarotid sodium amobarbital (ISA) procedure; however, since the hippocampus is not completely irrigated by the internal carotid artery, some believe the procedure may be invalid for memory testing. We quantified delta activity in intracerebral EEGs during ISA tests. There was increased delta in ipsilateral structures as follows: amygdala (6.4 minutes), anterior hippocampus (7.2), middle hippocampus (7.4), temporal neocortex (9.1), frontal lobe (8.4), central/parietal area (11.0), and occipital lobe (9.7). Contralateral structures usually (> 64%) showed increased delta lasting 4 to 5 minutes. The ipsilateral hippocampus had delta waves in over 90% of injections. We conclude that the hippocampus is clearly affected by the ISA injection. We argue that the slow waves may not be caused by a direct effect of the drug, but rather by a functional deafferentation due to the profound inactivation of structures surrounding the hippocampus. Similarly, slow waves contralateral to injection may be caused by sudden removal of neuronal input from the regions receiving the amobarbital.

MRI volumetric measurement of amygdala and hippocampus in temporal lobe epilepsy.

We performed MRI volumetric measurements of the amygdala (AM), the hippocampal formation (HF), and the anterior temporal lobe in a group of 30 patients with intractable temporal lobe epilepsy (TLE) and in seven patients with extratemporal lobe foci. Measurements were analyzed with a semiautomated software program and the results compared with those of normal controls and correlated with the findings of all other investigations. In particular, we compared the results with the lateralization of epileptic abnormalities in the EEG. Volumetric studies of AM and HF showed lateralization of measurable atrophy consistent with that derived from extracranial and intracranial EEG examinations. The HF volumes were more sensitive and provided a lateralization in 87%. Combined measurements of AM and HF showed lateralization in 93%, always congruent with the results of EEG lateralization. This slight but important additional improvement in discrimination justifies using AM measurements in MRI volumetric studies of mesial temporal structures. Volumetric studies combined with other currently employed noninvasive techniques may diminish the need for invasive methods of investigation in patients with TLE.

Early childhood prolonged febrile convulsions, atrophy and sclerosis of mesial structures, and temporal lobe epilepsy: an MRI volumetric study.

We performed MRI volumetric measurements of the amygdala (AM) and hippocampal formation (HF) in a group of 43 patients with temporal lobe epilepsy not controlled by optimal drug treatment. Fifteen patients (35%) had a history of prolonged febrile convulsions (PFC) in early childhood; 30 patients underwent surgery, and histopathology was available in twenty-four. The mean values of AM and HF volumes ipsilateral to the EEG focus were significantly smaller than those of normal controls. The volumetric measurements showed a more pronounced atrophy of the AM in patients with a history of PFC, although the HF volumes were also smaller in this group. Patients with a history of PFC had a higher proportion of more severe mesial temporal sclerosis (MTS) compared with those with no PFC. These findings confirm a correlation between early childhood PFC, the severity of atrophy of mesial structures, and MTS.

Anatomic basis of amygdaloid and hippocampal volume measurement by magnetic resonance imaging.

Both the amygdala and the hippocampus are involved in the pathogenesis of a number of neurologic conditions, including temporal lobe epilepsy, postanoxic amnesia, and Alzheimer's disease. To enhance the investigation and management of patients with these disorders, we developed a protocol to measure the volumes of the amygdala and as much of the hippocampus as possible (approximately 90 to 95%) using high-resolution MRI. We present the anatomic basis of these two protocols and our results in normal control subjects. These volumetric studies of the amygdala may clarify the role of this structure in the pathogenesis of temporal lobe epilepsy.

Regional cerebral blood flow and language dominance: SPECT during intracarotid amobarbital testing.

We examined the relation between language dominance and regional cerebral blood flow (rCBF) during the intracarotid amobarbital procedure (IAP). A previous report limited to three patients suggested that dominant rather than nondominant hemisphere IAP may have a differential effect on rCBF. Behavioral assessment during the IAP also suggests that dominant hemisphere injection results in a differential effect on memory and affective symptoms rather than nondominant injection. Thirteen patients were assessed using single-photon emission CT (SPECT) brain imaging during both left and right IAP. The SPECTs were coregistered with the individual's MRI. Changes in rCBF during each IAP were compared with the patient's baseline SPECT. Nine patients had left hemisphere dominance, two were right dominant, and two had bilateral speech representation. In the left dominant subjects, left-hemisphere injection had a consistently greater effect on rCBF than right-hemisphere injection in the anterior (p < 0.005) and posterior (p < 0.01) temporal neocortex. There was also a trend for greater hypoperfusion in the frontal lobe of the left hemisphere. rCBF in the ipsilateral hippocampus was not significantly different after each injection (p > 0.05). In the two patients with right hemisphere speech, the reverse pattern was seen, with greater hypoperfusion after right (dominant) hemisphere injection. There was no consistent asymmetry in the two patients with bilateral speech. Dominant hemisphere IAP results in significantly greater hypoperfusion than does nondominant injection. These data provide a physiologic basis for behavioral differences noted after dominant versus nondominant IAP.

Memory for designs: the hippocampal contribution.

The role of mesial temporal-lobe structures in the recall of designs was examined in two experiments. Normal control subjects and patients with right or left temporal lobectomy that included either a large or small excision from the hippocampal zone were tested. In Experiment 1, subjects copied a complex drawing that was presented piecemeal in an illogical order; in Experiment 2 they copied 18 individual designs. In both cases recall was tested 45 min later. Patients with right temporal lobectomy showed deficient recall in both experiments; in Experiment 1 only, patients with a large right hippocampal removal were also significantly impaired compared to those with a small removal.

Right hippocampal excision impairs learning and recall of a list of abstract designs.

The role of the temporal lobes and the hippocampus in learning a list of abstract designs was investigated. Variables studied included trials to criterion, 24-hr delayed recall and serial-position effects. Normal control subjects and four groups of patients, classified according to side of temporal lobectomy and extent of excision from the hippocampal zone, were tested. Patients with a right temporal lobectomy that included a large hippocampal excision showed deficient learning and memory, and, on the serial-position analysis, they recalled essentially none of the first items of the list. The other patient groups were unimpaired, except in the number of trials required to reach criterion.

Olfactory identification deficits in patients with focal cerebral excision.

The ability to identify common odors using the University of Pennsylvania Smell Identification Test was investigated in 120 patients with a focal surgical brain lesion and 20 normal control subjects. Results showed significant impairment after right or left temporal lobectomy, right or left frontal lobectomy, and right frontotemporal excision. Patients whose excision was confined to the left central, parietal or posterior area showed no significant deficit. The impairment after frontal lobectomy was demonstrated only in patients whose frontal-lobe removal invaded the orbital cortex; that group also showed a significantly greater impairment than did the temporal lobectomy group. All patient groups showed normal detection thresholds for n-butyl alcohol.

Learning and retention of words and designs following excision from medial or lateral temporal-lobe structures.

We sought to elucidate the contributions of the amygdala, hippocampus and temporal neocortex to learning and memory for verbal and visuospatial material. Two matched learning tasks, using abstract words versus abstract designs, were administered to patients with unilateral neocorticectomy (NCE; Dublin), selective amygdalohippocampectomy (AHE; Zurich) or anterior temporal-lobe resection invading the amygdala and hippocampus (ATL; Montreal). Data were analysed according to side and type of resection. Learning and recall for words was impaired in groups with resection from the left temporal lobe, irrespective of whether mediobasal structures were spared or temporal neocortex was spared. All right-resection groups were unimpaired. Learning for abstract designs was impaired across all trials in the right AHE and NCE groups, and on the last two trials in the right ATL group. Restricted deficits of lower magnitude were observed on some trials in left-resection groups. These results show a partial dissociation between side of excision and type of material, but the finding of similar deficits in all resection types was unexpected. We propose that excision from either the hippocampal region or temporal neocortex may result in a disconnection, giving a similar functional outcome, as both types of resection interrupt a circuit likely to be essential for normal storage and retrieval of information.

Human brain function during odor encoding and recognition. A PET activation study.

In previous positron emission tomography (PET) studies we have shown significant regional cerebral blood flow (rCBF) increases during olfactory stimulation: unilaterally in the right orbitofrontal cortex, and bilaterally in the inferior frontal and temporal lobes (piriform cortex). In the present study we investigated brain function during different stages of olfactory memory processing. Subjects were scanned during four tasks: odor encoding, long-term odor recognition, short-term odor recognition and a no-odor sensorimotor control task. Subjects were 12 right-handed healthy volunteers (6 men, 6 women). Each subject underwent a training session four days prior to their PET scan to learn the six odors required for the long-term memory scan. PET scans were obtained with a Siemens Exact ECAT HR+ 3D system using H2(15)O methodology and 60-sec scanning intervals. PET images were coregistered with each subject's magnetic resonance imaging scan, averaged, and transformed into standard stereotaxic space. Paired image subtractions were analyzed for rCBF changes. Preliminary analyses have revealed significant activation of the right orbitofrontal region and bilateral piriform cortices during the long-term odor recognition task compared with the control task. Activation of the right piriform cortex was present during the short-term recognition task. Brain activity during encoding and retrieval tasks also involved prefrontal cortices. PET activation studies of memory in other modalities have led to hypotheses of a hemispheric encoding/retrieval asymmetry in frontal cortex; the generalizability of this theory to olfactory memory will be discussed.

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.

Flavor processing: more than the sum of its parts.

We used positron emission tomography to evaluate differential processing of olfactory, gustatory and combined olfactory and gustatory (flavor) stimuli as indicated by comparison of evoked cerebral blood flow (CBF) changes during these conditions. We found significant CBF decreases in primary gustatory and secondary gustatory and olfactory cortices during simultaneous presentation compared with independent presentations of identical stimuli, suggesting that flavor processing is not represented by a simple convergence of its component senses. Additionally, CBF increases in the amygdala and basal forebrain were observed in a mismatched flavor condition versus a matched flavor condition, suggesting a role for these structures in processing novel or unpleasant stimuli.

Human cortical gustatory areas: a review of functional neuroimaging data.

In an effort to define human cortical gustatory areas we reviewed functional neuroimaging data for which coordinates standardized in Talairach proportional space were available. We observed a wide distribution of peaks within the insula and parietal and frontal opercula, suggesting multiple gustatory regions within this cortical area. Multiple peaks also emerged in the orbitofrontal cortex. However, only two peaks, both in the right hemisphere, were observed in the caudolateral orbitofrontal cortex, the region likely homologous to the secondary taste area described in monkeys. Overall significantly more peaks originated from the right hemisphere suggesting asymmetrical cortical representation of taste favoring the right hemisphere.

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%).

Incidental learning of image-mediated or pronounced words after right temporal lobectomy.

The use of visual images in word recall by patients with right temporal lobectomy was studied by testing the incidental learning of 40 (20 abstract, 20 concrete) words that had been either carefully pronounced or the referent visualized. When tested immediately after presentation of the list, the right temporal-lobe group (N = 30) did not differ from a matched normal control group, but in delayed recall 2 hours later the patient group showed impaired recall of concrete words that had been visualized. Recall of visualized abstract words was also poor but not significantly so, while pronounced words, whether abstract or concrete, were recalled normally. Further analysis revealed an impaired recall for visualized concrete words in both immediate and delayed testing in patients having a large right hippocampal removal, indicating an important role of the mesial temporal structures in image recall.