Cognitive training in Alzheimer's disease: a controlled randomized study.

This controlled randomized single-blind study evaluated the effects of cognitive training (CT), compared to active music therapy (AMT) and neuroeducation (NE), on initiative in patients with mild to moderate Alzheimer's disease (AD). Secondarily, we explored the effects of CT on episodic memory, mood, and social relationships. Thirty-nine AD patients were randomly assigned to CT, AMT, or NE. Each treatment lasted 3 months. Before, at the end, and 3 months after treatment, neuropsychological tests and self-rated scales assessed initiative, episodic memory, depression, anxiety, and social relationships. At the end of the CT, initiative significantly improved, whereas, at the end of AMT and NE, it was unchanged. Episodic memory showed no changes at the end of CT or AMT and a worsening after NE. The rates of the patients with clinically significant improvement of initiative were greater after CT (about 62%) than after AMT (about 8%) or NE (none). At the 3-month follow-up, initiative and episodic memory declined in all patients. Mood and social relationships improved in the three groups, with greater changes after AMT or NE. In patients with mild to moderate AD, CT can improve initiative and stabilize memory, while the non-cognitive treatments can ameliorate the psychosocial aspects. The combining of CT and non-cognitive treatments may have useful clinical implications.

Lack of habituation of evoked visual potentials in analytic information processing style: evidence in healthy subjects.

Habituation is considered one of the most basic mechanisms of learning. Habituation deficit to several sensory stimulations has been defined as a trait of migraine brain and also observed in other disorders. On the other hand, analytic information processing style is characterized by the habit of continually evaluating stimuli and it has been associated with migraine. We investigated a possible correlation between lack of habituation of evoked visual potentials and analytic cognitive style in healthy subjects. According to Sternberg-Wagner self-assessment inventory, 15 healthy volunteers (HV) with high analytic score and 15 HV with high global score were recruited. Both groups underwent visual evoked potentials recordings after psychological evaluation. We observed significant lack of habituation in analytical individuals compared to global group. In conclusion, a reduced habituation of visual evoked potentials has been observed in analytic subjects. Our results suggest that further research should be undertaken regarding the relationship between analytic cognitive style and lack of habituation in both physiological and pathophysiological conditions.

" The times they aren't a-changin' " rTMS does not affect basic mechanisms of temporal discrimination: a pilot study with ERPs.

In time processing, the role of different cortical areas is still under investigation. Event-related potentials (ERPs) represent valuable indices of neural timing mechanisms in the millisecond-to-second domain. We used an interference approach by repetitive TMS (rTMS) on ERPs and behavioral performance to investigate the role of different cortical areas in processing basic temporal information. Ten healthy volunteers were requested to decide whether time intervals between two tones (S1-S2, probe interval) were shorter (800ms), equal to, or longer (1200ms) than a previously listened 1000-ms interval (target interval) and press different buttons accordingly. This task was performed at the baseline and immediately after a 15-min-long train of 1-Hz rTMS delivered over the supplementary motor area, right posterior parietal cortex, right superior temporal gyrus, or an occipital control area. Task accuracy, reaction time, and ERPs during (contingent negative variation, CNV) and after the presentation of probe intervals were analyzed. At the baseline, CNV amplitude was modulated by the duration of the probe interval. RTMS had no significant effect on behavioral or ERP measures. These preliminary data suggest that stimulated cortical areas are less crucially involved than other brain regions (e.g. subcortical structures) in the explicit discrimination of auditory time intervals in the range of hundreds of milliseconds.

Music and emotion: an EEG connectivity study in patients with disorders of consciousness.

Human emotion perception is a topic of great interest for both cognitive and clinical neuroscience, but its electrophysiological correlates are still poorly understood. The present study is aimed at evaluating if measures of synchronization and indexes based on graph-theory are a tool suitable to study and quantify electrophysiological changes due to emotional stimuli perception. In particular, our study is aimed at evaluating if different EEG connectivity patterns can be induced by pleasant (consonant) or unpleasant (dissonant) music, in a population of healthy subjects, and in patients with severe disorders of consciousness (DOCs), namely vegetative state (VS) patients. In the control group, pleasant music induced an increase in network number of connections, compared with the resting condition, while no changes were caused by the unpleasant stimuli. However, clustering coefficient and path length, two indexes derived from graph theory, able to characterise segregation and integration properties of a network, were not affected by the stimuli, neither pleasant nor unpleasant. In the VS group, changes were found only in those patients with the less severe consciousness impairment, according to the clinical assessment. In these patients a stronger synchronization was found during the unpleasant condition; moreover we observed changes in the network topology, with decreased values of clustering coefficient and path length during both musical stimuli.Our results show that measures of synchronization can provide new insights into the study of the electro physiological correlates of emotion perception, indicating that these tools can be used to study patients with DOCs, in whom the issue of objective measures and quantification of the degree of impairment is still an open and unsolved question.

Event-related potential (ERP) markers of melodic processing: The N2 component is modulated by structural complexity, not by melodic 'meaningfulness'.

Previous studies have demonstrated that the event-related potential (ERP) evoked by a note shows substantial differences depending on whether the note is part of a melodic context or presented in an unstructured repetition. In particular, the N2 component has been found to have considerably increased latency and a more frontal topography for notes presented in a melody. An open question is whether such effect is related to the 'meaningfulness' of a note sequence, that is due to the formation of abstract melodic entities, rather than more simply an indicator of cognitive load associated with processing a structurally-complex sequence as opposed to an unstructured repetition. In this study, we addressed this issue by recording ERPs from 10 healthy non-musicians listening to eight one-part unfamiliar tonal melodies and eight sequences of random notes. The two stimuli were matched for distribution of pitch, intervals and note duration as well as for entropy of the time-series of pitch and duration. While tonal melodies were rated more meaningful (p<0.001) and pleasant (p<0.001) by all participants, no effects were found for the N2 component amplitude (p> or =0.8) and latency (p=0.2). Combined with previous findings, this indicates that the N2 evoked by each individual note responds to the structural complexity of the note sequence, i.e., to the presence of pitch and duration changes, but not to higher-level processing related to the formation of abstract melodic entities. In contrast, we found that the amplitude of the P2 component was marginally (p=0.04) elevated for random notes as compared to tonal melodies. This may be related to attentional modulation, or more specifically to associative components of auditory processing.

Photosensitive epilepsy: spectral and coherence analyses of EEG using 14Hz intermittent photic stimulation.

OBJECTIVE: To evaluate the EEG recorded in photosensitive idiopathic generalised epilepsy (IGE) patients at rest and during 14Hz IPS, frequency capable of inducing photoparoxysmal responses (PPRs). METHODS: Power spectrum density and coherence profiles were estimated using a block autoregressive parametric model (AR) in 28 patients and 22 controls. RESULTS: At rest, the intra- and inter-hemispheric coherence spectra showed a significantly larger number of coherence peaks in the gamma band in patients with respect to controls. During intermittent photic stimulation (IPS), coherent gamma activity is mainly presented as IPS frequency harmonics; moreover, the patients' mean coherence values significantly increased. In six patients re-evaluated with IPS after putting on glasses with Z1 blue lens (which counteracts PPR) the spectral and coherence profiles tended to return to the resting ones. CONCLUSIONS: Patients are endowed with inherited EEG hyper-synchrony as shown by the large number of coherence peaks detectable under resting conditions, whereas IPS enhances intra- and inter-hemispheric mean coherence values in the gamma band. The persistence of alpha activity peaks during IPS in most controls but not in patients suggests that the alpha generating network plays a significant role in counteracting PPR. SIGNIFICANCE: Both gamma and alpha EEG generators are involved in the PPR generation and in the widespread synchronisation characterising the IGE-associated photosensitivity.

Preserved memory in temporal lobe epilepsy patients after surgery for low-grade tumour. A pilot study.

The objective was to carry out a pilot study exploring memory outcome in patients with temporal lobe epilepsy (TLE) and low-grade tumour. A prospective study using a competence-related memory assessment was carried out in the Laboratory of Neuropsychology, Epilepsy Center and Neurosurgical Department of the "C. Besta" National Neurological Institute in 24 TLE patients undergoing surgical resection for left (n=12) or right (n=12) low-grade tumours and 36 healthy subjects. Patients underwent mesial or lateral temporal lobe lesionectomy. Neuropsychological tests exploring verbal and visual short-term memory, learning, delayed recall and ability to control interference in memory were applied. Before and after surgery, significant verbal impairment was present in left TLE patients compared to controls and right TLE patients, and visual deficits were present in both groups compared to controls. After surgery, there was no significant decrease in mean verbal or visual memory scores related to the operated side. Some memory abilities subserved by the contralateral temporal lobe improved. Postoperative memory scores were related to preoperative scores, side of operation, age and education. In patients with TLE and low-grade tumour, temporal lobe surgery does not necessarily induce memory deficits. Improvement of memory abilities subserved by the unoperated temporal lobe may be expected.

Phosphorylation of sodium channels mediated by protein kinase-C modulates inhibition by topiramate of tetrodotoxin-sensitive transient sodium current.

BACKGROUND AND PURPOSE: Topiramate is a novel anticonvulsant known to modulate the activity of several ligand- and voltage-gated ion channels in neurons. The mechanism of action of topiramate, at a molecular level, is still unclear, but the phosphorylation state of the channel/receptor seems to be a factor that is able to influence its activity. We investigated the consequences of phosphorylation of the sodium channel on the effect of topiramate on tetrodotoxin (TTX)-sensitive transient Na(+) current (I(NaT)). EXPERIMENTAL APPROACH: I(NaT) was recorded in dissociated neurons of rat sensorimotor cortex using whole-cell patch-clamp configuration. KEY RESULTS: We found that topiramate (100 microM) significantly shifted the steady-state I(NaT) inactivation curve in a hyperpolarized direction. In neurons pre-treated with a PKC-activator, 1-oleoyl-2-acetyl-sn-glycerol (OAG; 2 microM), the net effect of topiramate on steady-state I(NaT) inactivation was significantly decreased. In addition, OAG also slightly shifted the I(NaT) activation curve in a hyperpolarized direction, while perfusion with topiramate had no effect on the parameters of I(NaT) activation. CONCLUSIONS AND IMPLICATIONS: These data show that PKC-activation can modulate the effect of topiramate on I(NaT). This suggests that channel phosphorylation in physiological or pathological conditions (such as epiliepsy), can alter the action of topiramate on sodium currents.

Novel NHLRC1 mutations and genotype-phenotype correlations in patients with Lafora's progressive myoclonic epilepsy.

BACKGROUND: Lafora's progressive myoclonic epilepsy (Lafora's disease) is an autosomal recessive neurodegenerative disorder characterised by the presence of polyglucosan intracellular inclusions called Lafora bodies. Mutations in two genes, EPM2A and NHLRC1, have been shown to cause the disease. A previous study showed mutations in the EPM2A gene in 14 Lafora's disease families and excluded the involvement of this gene in five other families who were biopsy proven to have the disease. OBJECTIVE: To relate the genetic findings to the clinical course of the disease. METHODS: As part of an ongoing mutational study of the Lafora's disease genes, five new families with the disease were recruited and the genetic analysis was extended to screen the entire coding region of the NHLRC1 gene. Genotype-phenotype correlations were carried out. RESULTS: Seven NHLRC1 mutations were identified, including five novel mutations (E91K, D195N, P218S, F216_D233del, and V359fs32), in eight families with Lafora's disease. On relating the genetic findings to the clinical course of the disease it was shown that patients with NHLRC1 mutations had a slower rate of disease progression (p<0.0001) and thus appeared to live longer than those with EPM2A mutations. A simple DNA based test is described to detect the missense mutation C26S (c.76T-->A) in the NHLRC1 gene, which is prevalent among French Canadians. CONCLUSIONS: Patients with NHLRC1 mutations have a slower rate of disease progression than those with EPM2A mutations.

Movement-related desynchronization-synchronization (ERD/ERS) in patients with Unverricht-Lundborg disease.

We studied changes in event-related desynchronization/synchronization (ERD/ERS) patterns in patients with Unverricht-Lundborg disease (ULD), presenting with prominent action myoclonus. We analyzed the movement-related ERD/ERS in alpha and beta frequency bands in 15 patients using self-paced finger extension as a motor paradigm and we compared the results with those obtained in 12 healthy volunteers. In all ULD patients, alpha- and beta-ERD regularly occurred with onset and location similar to that found in healthy controls, but the desynchronization of alpha activity was significantly greater than in controls (C3: -64.4+/-9.8% vs. -49.7+/-14.8%; p=0.004). Moreover, in the patients, both alpha- and beta-ERD spread toward frontal electrodes. In controls, the post-movement beta-ERS regularly occurred; it was absent in eight patients with severe action myoclonus, while, in seven patients with mild or moderate myoclonus, the beta-peak was significantly smaller with respect to that measured in controls (55.6+/-15.1% vs. 153.9+/-99.8%, p=0.006). The failure of beta-ERS well-correlated with motor impairment resulting from action myoclonus, whereas SSEPs and long-loop reflexes performed to detect signs of cortical hyperexcitability showed inconsistent changes. In ULD patients, ERD/ERS changes indicate an increased activation of motor cortex during movement planning and a great reduction of post-excitatory inhibition of motor cortex. The changes involving beta-ERS had a significant relationship with the functional disability in individual patients and might play a pathogenic role in the motor dysfunction.

Layer-specific properties of the persistent sodium current in sensorimotor cortex.

We evaluated the characteristics of the persistent sodium current (I(NaP)) in pyramidal neurons of layers II/III and V in slices of rat sensorimotor cortex using whole cell patch-clamp recordings. In both layers, I(NaP) began activating around -60 mV and was half-activated at -43 mV. The I(NaP) peak amplitude and density were significantly higher in layer V. The voltage-dependent I(NaP) steady-state inactivation occurred at potentials that were significantly more positive in layer V (V(1/2): -42.3 +/- 1.1 mV) than in layer II/III (V(1/2): -46.8 +/- 1.6 mV). In both layers, a current fraction corresponding to about 25% of the maximal peak amplitude did not inactivate. The time course of I(NaP) inactivation and recovery from inactivation could be fitted with a biexponential function. In layer V pyramidal neurons the faster time constant of development of inactivation had variable values, ranging from 158.0 to 1,133.8 ms, but it was on average significantly slower than that in layer II/III (425.9 +/- 80.5 vs. 145.8 +/- 18.2 ms). In both layers, I(NaP) did not completely inactivate even with very long conditioning depolarizations (40 s at -10 mV). Recovery from inactivation was similar in the two layers. Layer V intrinsically bursting and regular spiking nonadapting neurons showed particularly prolonged depolarized plateau potentials when Ca2+ and K+ currents were blocked and slower early phase of I(NaP) development of inactivation. The biexponential kinetics characterizing the time-dependent inactivation of I(NaP) in layers II/III and V indicates a complex inactivating process that is incomplete, allowing a residual "persistent" current fraction that does not inactivate. Moreover, our data indicate that I(NaP) has uneven inactivation properties in pyramidal neurons of different layers of rat sensorimotor cortex. The higher current density, the rightward shifted voltage dependency of inactivation as well the slower kinetics of inactivation characterizing I(NaP) in layer V with respect to layer II/III pyramidal neurons may play a significant role in their ability to fire recurrent action potential bursts, as well in the high susceptibility to generate epileptic events.

Unilateral frontal lobe epilepsy affects executive functions in children.

Very few studies to date have investigated the neuropsychological changes detectable in children suffering from frontal lobe epilepsy (FLE). The aim of the present study was to assess the effects of FLE on cognitive and executive functions in childhood. The sample includes 17 children with a frontal epileptogenic focus (10 right and 7 left), with no evidence of anatomical brain damage. These subjects were assessed by means of a battery of tests to investigate executive functioning. The results emphasised the presence of selective impairments of frontal lobe functions without evidence of deficits in global intellectual functioning. No side-specific deficits were detected, while an earlier onset of epilepsy and the duration of the disorder, but not the seizures frequency, were found to correspond with more severe deficits in some specific frontal lobe functions.

FVEPs in Creutzfeldt-Jacob disease: waveforms and interaction with the periodic EEG pattern assessed by single sweep analysis.

OBJECTIVE: To characterise flash visual evoked potentials (FVEPs) in 20 patients with Creutzfeldt-Jacob disease (CJD), and assess the relationships between spontaneous EEG patterns and the responses to individual stimuli. METHODS: We analysed the shape and time course of periodic sharp wave complexes (PSWCs) and responses to 1 Hz flashes. In nine patients, we applied an algorithm based on an autoregressive model with exogenous input (ARX) to estimate responses to individual random flashes and their interaction with PSWCs. RESULTS: The FVEPs included P1 and N1 components in all patients, and the P2 peak in 18. Eight patients showed giant FVEPs (N1-P2>60 V), all of whom had an MM polymorphism in codon 129 of the prion protein gene; in seven cases, the presence of giant FVEPs correlated with a prominent and almost continuous periodic EEG pattern. Giant N1-P2 abnormally spread on the anterior scalp regions, and had a different waveform distribution from that of the PSWCs. In five patients with a normal or slightly enlarged average N1-P2 amplitude, single sweep (ARX) analysis revealed a period of relative refractoriness following individual PSWCs. In four patients with 'giant' FVEPs, the individual responses occurred regardless of the interval between the stimulus and previous PSWC, but their amplitude had an inverse relationship with the interval length. CONCLUSIONS: Giant responses to flash stimuli are a common finding in CJD patients (40% of our cases). Single sweep ARX analysis showed that PSWCs were followed by a period of partial refractoriness, which prevented most of the individual responses to flashes, but not giant FVEPs. The association between prominent spontaneous paroxysms and giant FVEPs suggests that both are due to a common hyperexcitable change favouring neuronal synchronisation. SIGNIFICANCE: Our data contribute to clarifying the debated problem of the occurrence of giant FVEPs in CJD and their relationships with the spontaneous periodic EEG pattern.

Sensorimotor cortex excitability in Unverricht-Lundborg disease and Lafora body disease.

OBJECTIVE: To investigate whether Unverricht-Lundborg disease (ULD) and Lafora body disease (LBD) can be differentiated on the basis of their neurophysiologic profiles. METHODS: Somatosensory evoked potentials (SSEPs), long-loop reflexes (LLRs), and the influence of conditioning nerve stimulation on the motor potentials evoked by transcranial stimulation in 8 patients with LBD and 10 patients with ULD were investigated. RESULTS: Both groups showed sensorimotor cortex hyperexcitability, but their electrophysiologic profiles were different. Enlarged P25 to N33 SSEP components and enhanced LLRs were common in the ULD patients, whereas medium-latency "giant" SSEP components and less consistently enhanced LLRs were more frequently found in the patients with LBD. Cortical relay time was extremely brief in ULD but varied in LBD. Conditioning somatosensory stimuli differently affected motor cortex excitability, leading to early facilitation in ULD and delayed and prolonged facilitation in LBD. CONCLUSIONS: Patients with Unverricht-Lundborg disease (ULD) and Lafora body disease (LBD) have different electrophysiologic profiles. The ULD findings point to an aberrant subcortical or cortical loop (possibly short-cutting the somatosensory cortex) that is involved in generating the prominent action myoclonus characterizing the disorder. The LBD findings highlight sustained hyperexcitability of the sensorimotor cortex in response to afferent stimuli, which fit with a more severe impairment of inhibitory mechanisms.

Subcortical nodular heterotopia: a functional MRI and somatosensory evoked potentials study.

Subcortical nodular heterotopia (SNH) associated with refractory epilepsy may be surgically treated, and a positive outcome can be expected following the complete excision of the malformed tissue. Recent functional neuroimaging studies have suggested the possible functional relevance of cerebral malformations, and may make it possible to improve presurgical planning, thus allowing extended resections and minimising post-operative deficits. We here report the case of a 19-year-old man with epilepsy and a giant SNH associated with diffused abnormal gyrations of the right temporal-parietal regions. Cortical functional organisation was investigated by means of functional magnetic resonance imaging (MRI) during sensory and motor tasks, and somatosensory evoked potentials. The results revealed enlarged and displaced motor and sensory cortical areas with heterotopic tissue functional activation. The relevance of these findings is discussed in the light of the possible surgical treatment of drug-refractory epilepsy associated with cerebral malformations: surgical treatment based on conventional MRI studies alone, without taking the functional nature of dysplastic tissues into account, may lead to considerable side effects.

Protein-kinase C-dependent phosphorylation inhibits the effect of the antiepileptic drug topiramate on the persistent fraction of sodium currents.

We investigated the interference of protein-kinase C (PKC)-dependent Na(+) channel phosphorylation on the inhibitory effect that the antiepileptic drug topiramate (TPM) has on persistent Na(+) currents (I(NaP)) by making whole cell patch-clamp and intracellular recordings of rat sensorimotor cortex neurons. The voltage-dependent activation of I(NaP) was significantly shifted in the hyperpolarizing direction when PKC was activated by 1-oleoyl-2-acetyl-sn-glycerol (OAG). TPM reduced the peak amplitude of I(NaP), but it did not counteract the OAG-induced shift in I(NaP) activation. Firing property experiments showed that the firing threshold was lowered by OAG. TPM was unable to counteract this effect, which may be due to OAG-dependent enhancement of the contribution of subthreshold I(NaP). These data suggest that PKC activation may limit the effect of the anticonvulsant TPM on the persistent fraction of Na(+) currents. The channel phosphorylation that may occur in cortical neurons as a result of physiological or pathological (e.g. epileptic) events can modulate the action of TPM on Na(+) currents.

Terminology and classification of the cortical dysplasias.

BACKGROUND: There have been difficulties in achieving a uniform terminology in the literature regarding issues of classification with respect to focal cortical dysplasias (FCDs) associated with epilepsy. OBJECTIVE: S: To review and refine the current terminology and classification issues of potential clinical relevance to epileptologists, neuroradiologists, and neuropathologists dealing with FCD. METHODS: A panel discussion of epileptologists, neuropathologists, and neuroradiologists with special expertise in FCD was held. RESULTS: The panel proposed 1) a specific terminology for the different types of abnormal cells encountered in the cerebral cortex of patients with FCD; 2) a reappraisal of the different histopathologic abnormalities usually subsumed under the term "microdysgenesis," and suggested that this terminology be abandoned; and 3) a more detailed yet straightforward classification of the various histopathologic features that usually are included under the heterogeneous term of "focal cortical dysplasia." CONCLUSION: The panel hopes that these proposals will stimulate the debate toward more specific clinical, imaging, histopathologic, and prognostic correlations in patients with FCD associated with epilepsy.

Cesare Lombroso, cortical dysplasia, and epilepsy: keen findings and odd theories.

BACKGROUND: Cesare Lombroso supported a common origin of criminality, genius, and epilepsy as caused by factors impairing the embryonic development of the CNS, mainly affecting the hierarchically superior neural centers. OBJECTIVE: To describe the first observations of cortical dysplasia in patients with epilepsy by Cesare Lombroso and his coworkers in 1896. RESULTS: To confirm his theories, Lombroso emphasized the need for the direct observation of the patient, using anthropologic, social, neurophysiologic, economic, and pathologic data. With the collaboration of his pupil Luigi Roncoroni, Lombroso described a prevalence of large, giant pyramidal neurons and polymorphous cells through the gray matter of the frontal cortex in 13 patients with epilepsy. Most of the large pyramidal neurons were haphazardly arranged, presenting also an abnormal orientation of their apical dendrites. The number of nervous cells was noticeably reduced, with the presence of abundant gliosis. Moreover, the granular layers were dramatically reduced or absent in most patients, and numerous nervous cells were present in the subcortical white matter. This particular finding was never observed in specimens from criminal and healthy control subjects. Lombroso and Roncoroni explained their finding as evidence of an arrest of CNS development. CONCLUSIONS: More than one century ago, Cesare Lombroso and collaborators described developmental lesions in the frontal cortex of patients with epilepsy, which correspond to what currently is called Taylor's dysplasia. However, they used their observations to support their scientific misconception on the relationship between criminality, epilepsy, and genius.