Personalised music as a treatment for epilepsy.

In this paper we look at non-pharmaceutical treatments for intractable epilepsy based on neurophysiological methods especially with EEG analysis. In summary, there are a number of limbic and thalamo-cortical related structures involved in the processing of musical emotion (exposure), including the amygdala (arousal, expression of mood, fear), hippocampus (memory, regulation of HPA axis, stress), parahippocampal gyrus (recognition, memory retrieval), insula (valence), temporal poles (connectivity), ventral striatum (expectation and experience of reward), orbitofrontal cortex (valence) and cingulate cortex (autonomic regulation). One method is to audify (a form of sonification) EEG activity to find music by feedback to entrain abnormal EEG activity. We discuss various methods and our use of X-System (https://www.x-system.co.uk/) which is a computational model of the musical brain capable of predicting the neurophysiological effects of music. It models structures and pathways related to responses to music, including the cochlea, brain stem, auditory and motor cortex, as well as basal ganglia, cerebellum and limbic structures. It can predict autonomic and endocrine activity as well as the substrates of electrical activity to select music which can regularise EEG abnormalities to decrease epileptic activity and seizures, especially in those unresponsive to antiepileptic medication or invasive treatments.

Prevalence, patterns, service needs, and assessment of neuropsychiatric disorders among people with epilepsy in residential care: validation of the Neuropsychiatric Inventory as a caregiver-rated measure of neuropsychiatric functioning in epilepsy.

We assessed 228 people with epilepsy (PWE) in the residential care setting using the Neuropsychiatric Inventory (NPI) and Brief Psychiatric Rating Scale (BPRS) as caregiver- and observer-rated instruments. There was a significant burden of psychopathology, about half of all subjects surveyed scoring positive on either or both instruments. Psychopathology as measured by the NPI and BPRS was significantly greater in cognitively impaired subjects than in those with intact cognitive function. The NPI was found to be a valid caregiver-rated measure of psychopathology in PWE, with a principal components analysis yielding a reliable and interpretable four-factor solution, psychosis, interictal dysphoric disorder, depression, and anxiety being identified. Mental health service needs were found to be considerable in this population, with a significant hidden burden of psychiatric comorbidity. As this population has ongoing service needs through the life span, further research is necessary.

Are patients with somatization disorder highly suggestible?

OBJECTIVE: High suggestibility is widely regarded as an important feature of patients with medically unexplained symptoms (MUS), particularly those with multiple MUS [i.e. somatization disorder (SD)], although there are few empirical data attesting to this assumption. A study was therefore conducted to compare levels of non-hypnotic suggestibility in patients with SD and medical controls. METHOD: A modified version of the Barber Suggestibility Scale was administered to 19 patients with SD and 17 controls with an established organic dystonia. RESULTS: Patients with SD were no more suggestible than control patients. Dystonia controls were more likely to deliberately comply with suggestions than the SD patients. CONCLUSION: Contrary to popular belief, high suggestibility is not necessarily a feature of SD.

The classification of neuropsychiatric disorders in epilepsy: a proposal by the ILAE Commission on Psychobiology of Epilepsy.

The classification of psychiatric disorders in epilepsy has evolved considerably from the first attempts in the 19th century. A dedicated subcommission of the ILAE Commission on Psychobiology of Epilepsy (now the Commission on Neuropsychiatric Aspects) has developed this classification proposal. The aim of this proposal is to separate disorders comorbid with epilepsy and those that reflect ongoing epileptiform activity from epilepsy-specific disorders, and to attempt to subclassify the epilepsy-specific disorders alone. Further, the classification of epilepsy-specific psychiatric disorders has largely followed their relationship to the ictus, with factors such as relationship to antiepileptic drug (AED) change being coded as additional information. Finally, this proposal presents a clinical and descriptive system of classification rather than an etiological classification on the grounds that there is currently inadequate information for the latter approach to be employed globally.

Friedrich Nietzsche's mental illness--general paralysis of the insane vs. frontotemporal dementia.

OBJECTIVE: For a long time it was thought that Nietzsche suffered from general paralysis of the insane (GPI). However, this diagnosis has been questioned recently, and alternative diagnoses have been proposed. METHOD: We have charted Friedrich Nietzsche's final fatal illness, and viewed the differential diagnosis in the light of recent neurological understandings of dementia syndromes. RESULTS: It is unclear that Nietzsche ever had syphilis. He lacked progressive motor and other neurological features of a progressive syphilitic central nervous system (CNS) infection and lived at least 12 years following the onset of his CNS signs, which would be extremely rare for patients with untreated GPI. Finally, his flourish of productivity in 1888 would be quite uncharacteristic of GPI, but in keeping with reports of burgeoning creativity at some point in the progression of frontotemporal dementia (FTD). CONCLUSION: We suggest that Nietzsche did not have GPI, but died from a chronic dementia, namely FTD.

Subthreshold rTMS over pre-motor cortex has no effect on tics in patients with Gilles de la Tourette syndrome.

OBJECTIVE: A previous study showed no effect of 1Hz repetitive transcranial magnetic stimulation (rTMS) on tics in Gilles de la Tourette Syndrome (GTS). We modified the rTMS protocol in order to investigate some of the possible methodological reasons for the negative outcome in that study. METHODS: In a single blinded placebo-controlled cross-over study in five GTS patients without obsessive compulsive disorder we probed whether longer trains (1800 stimuli) of 1 Hz pre-motor cortex rTMS at 80% of active motor threshold and application to both hemispheres can improve tics in GTS. This was measured with the Yale Global Tic severity rating scale, the MOVES self-rating scale and video analysis. RESULTS: We found no significant effect of either left pre-motor cortex stimulation alone, or left pre-motor followed by right pre-motor cortex stimulation. CONCLUSIONS: These results suggest that the rTMS protocol used in this study is not useful for the treatment of tics in GTS. SIGNIFICANCE: rTMS protocols need to be modified substantially in order to explore their potential for the treatment of tics in GTS.

Mirtazapine increases cortical excitability in healthy controls and epilepsy patients with major depression.

BACKGROUND: Epilepsy is often complicated by depression requiring antidepressant treatment. Such treatment might be proconvulsive. OBJECTIVE: To examine the effects of the noradrenergic and specific serotonergic antidepressant mirtazapine on motor cortex excitability in epilepsy patients with depression and in healthy controls, using transcranial magnetic stimulation (TMS). METHODS: Seven clinically depressed epilepsy patients treated with anticonvulsant drugs and six healthy volunteers were studied. Before intake of mirtazapine and 24 hours afterwards (and also three weeks afterwards in the patients), the active and resting motor threshold (AMT, RMT), the size of the motor evoked potential (MEP), the cortical silent period (SP), and intracortical inhibition/facilitation and intracortical facilitatory I wave interactions were determined using single and paired pulse TMS. RESULTS: At baseline, AMT and RMT were higher (p = 0.049 and p = 0.04, respectively) and the ratio SP duration/MEP area greater in patients (p = 0.041). In patients but not in healthy subjects AMT was lower 24 hours after intake of mirtazapine (p = 0.028). Mirtazapine had no significant effect on the MEP size, duration of the SP, or the ratio of SP duration to MEP size in patients. The duration of the SP was longer (p = 0.037) but the ratio of SP duration to MEP size remained similar in healthy subjects after mirtazapine. There were no significant differences in paired pulse measures between the two groups either at baseline or after mirtazapine. CONCLUSIONS: Mirtazapine increased neuronal excitability of pyramidal tract axons in an activated state in both healthy controls and epilepsy patients with major depression.

Chronic antidopaminergic medication might affect amygdala structure in patients with schizophrenia.

BACKGROUND: Recently amygdala enlargement has been reported in patients with schizophrenia like psychosis of epilepsy. The effect of antipsychotic medication on amygdala structure has not been investigated so far. There is theoretical evidence to support the assumption that dopaminergic neurotransmission might affect neuronal plasticity. METHODS: In order to analyze the influence of chronic antidopaminergic medication on amygdala structure we compared amygdala volumes in patients with schizophrenia like psychosis of epilepsy (POE) treated with neuroleptic medication (n = 11) to patients with POE not treated with such medication (n = 15), patients with epilepsy alone (n = 24) and healthy control subjects (n = 20). RESULTS: Analyzing our data with a factorial ANOVA approach, we found a significant effect of the factor medication in that patients treated with antipsychotic medication displayed a "normalization" of the increased amygdala volumes observed in the untreated patient group. CONCLUSION: This observation supports the assumption that antidopaminergic medication might affect the amygdala structure.

The psychiatric comorbidity of epilepsy.

Several studies have assessed the prevalence of psychiatric disorders in epilepsy. They are characterized by considerable heterogeneity, because of differences in the population setting and type of study. A non-systematic review of the literature allows us to draw some useful, although not definite, conclusions. Six per cent of people with epilepsy in the general population appear to suffer from a psychiatric disorder, while this rises to 10-20% in populations with temporal lobe and/or refractory epilepsy. Mood disorders are the most common culprit (24-74%), particularly depression (30%), followed by anxiety disorders (10-25%), psychoses (2-7%) and personality disorders (1-2%). This comorbidity appears to be related to endogenous and exogenous (including iatrogenic) factors and to the severity and chronicity of epilepsy. Conditions such as schizophrenia-like psychosis of epilepsy and interictal dysphoric disorder are represented only in epilepsy. Adequate recognition and treatment of psychiatric conditions in epilepsy is essential for patient management because of their considerable burden in morbidity and quality of life.

Activity in ventromedial prefrontal cortex covaries with sympathetic skin conductance level: a physiological account of a "default mode" of brain function.

We examined neural activity related to modulation of skin conductance level (SCL), an index of sympathetic tone, using functional magnetic resonance imaging (fMRI) while subjects performed biofeedback arousal and relaxation tasks. Neural activity within the ventromedial prefrontal cortex (VMPFC) and the orbitofrontal cortex (OFC) covaried with skin conductance level (SCL), irrespective of task. Activity within striate and extrastriate cortices, anterior cingulate and insular cortices, thalamus, hypothalamus and lateral regions of prefrontal cortex reflected the rate of change in electrodermal activity, highlighting areas supporting transient skin conductance responses (SCRs). Successful performance of either biofeedback task (where SCL changed in the intended direction) was associated with enhanced activity in mid-OFC. The findings point to a dissociation between neural systems controlling basal sympathetic tone (SCL) and transient skin conductance responses (SCRs). The level of activity in VMPFC has been related to a default mode of brain function and our findings provide a physiological account of this state, indicating that activity within VMPFC and OFC reflects a dynamic between exteroceptive and interoceptive deployment of attention.

Reliability of self-reported diagnoses in patients with neurologically unexplained symptoms.

BACKGROUND: Patients with neurologically unexplained symptoms (NUS) often have a previous history of other medically unexplained symptoms. A past history of such symptoms can help make a positive diagnosis of a somatoform or affective disorder, and enable appropriate management strategies. However, information on past medical diagnoses is primarily obtained from patient interviews and may be inaccurate, particularly in patients with NUS. OBJECTIVE: To assess the reliability of past medical diagnoses reported by patients with NUS compared with patients with confirmed neurological disease (ND) without suspicion of somatoform illness. METHODS: 21 patients with NUS and 16 patients with ND were interviewed about their current and past medical problems and diagnoses. The accuracy of the reported diagnoses was assessed through examination of their complete general practice notes. RESULTS: The median number of previous diagnoses reported by patients with NUS was significantly higher than in controls (7 v 3, p = 0.001). There was no difference in the median number of confirmed diagnoses between the two groups (2 v 2.5); however, the median percentage of reported diagnoses confirmed by investigations was significantly smaller in the NUS group (22% v 80%, p = 0.001). The additional diagnoses reported by patients with NUS not only comprised functional syndromes such as irritable bowel syndrome or non-cardiac chest pain (6% v 0%, p = 0.01), but also organic diagnoses which had either been unequivocally excluded (5% v 0%, p = 0.006), were based on equivocal findings often found after multiple investigations (9% v 0%, p = 0.01), or had not been investigated before a clinical diagnosis was made (50% v 18%, p = 0.04). CONCLUSION: Reported previous diagnoses should not be taken at face value when the current differential diagnosis includes a functional/somatoform neurological syndrome, particularly if the list of past medical diagnoses is long. Confirmation of previous diagnoses from alternative sources may contribute to a diagnosis of somatoform disorder, allowing appropriate management strategies for the current (and past) complaints to be initiated.

Religiosity is associated with hippocampal but not amygdala volumes in patients with refractory epilepsy.

OBJECTIVE: To assess the relationship between the behavioural triad of hyper-religiosity, hypergraphia and hyposexuality in epilepsy, and volumes of the mesial temporal structures. METHOD: Magnetic resonance images were obtained from 33 patients with refractory epilepsy and mesial temporal structure volumes assessed. Amygdala and hippocampal volumes were then compared in high and low scorers on the religiosity, writing, and sexuality sub-scales of the Neurobehavioural Inventory. RESULTS: Patients with high ratings on the religiosity scale had significantly smaller right hippocampi. Religiosity scores rated by both patient and carer showed a significant negative correlation with right hippocampal volumes in this group. There were no other differences in amygdala or hippocampal volumes between these groups, or between high and low scorers on the writing and sexuality sub-scales. CONCLUSIONS: These findings suggest that right hippocampal volumes are negatively correlated with religiosity in patients with refractory epilepsy.

Brain activity relating to the contingent negative variation: an fMRI investigation.

The contingent negative variation (CNV) is a long-latency electroencephalography (EEG) surface negative potential with cognitive and motor components, observed during response anticipation. CNV is an index of cortical arousal during orienting and attention, yet its functional neuroanatomical basis is poorly understood. We used functional magnetic resonance imaging (fMRI) with simultaneous EEG and recording of galvanic skin response (GSR) to investigate CNV-related central neural activity and its relationship to peripheral autonomic arousal. In a group analysis, blood oxygenation level dependent (BOLD) activity during the period of CNV generation was enhanced in thalamus, somatomotor cortex, bilateral midcingulate, supplementary motor, and insular cortices. Enhancement of CNV-related activity in anterior and midcingulate, SMA, and insular cortices was associated with decreases in peripheral sympathetic arousal. In a subset of subjects in whom we acquired simultaneous EEG and fMRI data, we observed activity in bilateral thalamus, anterior cingulate, and supplementary motor cortex that was modulated by trial-by-trial amplitude of CNV. These findings provide a likely functional neuroanatomical substrate for the CNV and demonstrate modulation of components of this neural circuitry by peripheral autonomic arousal. Moreover, these data suggest a mechanistic model whereby thalamocortical interactions regulate CNV amplitude.

Dopamine transporter binding in Gilles de la Tourette syndrome: a [123I]FP-CIT/SPECT study.

OBJECTIVE: To investigate dopamine transporter binding in Gilles de la Tourette syndrome (GTS) with SPECT and [123I]FP-CIT. METHOD: Ten neuroleptic naïve/free patients with GTS, and 10 age- and gender-matched normal volunteers were studied. Subjects were clinically evaluated. GTS severity and affective symptoms were measured and the presence of GTS-related behaviours were recorded. RESULTS: The GTS group showed significantly higher binding in both caudate and putamen nuclei than the controls. No associations were found between striatal binding ratios and measures of affect or GTS-related behaviours. CONCLUSION: Patients with GTS show higher striatal binding of FP-CIT to the striatum in comparison with age- and gender-matched control subjects, indicating that dopamine transporter abnormalities are involved in the pathophysiology of GTS. These abnormalities appear to be distributed across both caudate and putamen.

Psychiatric adverse events during levetiracetam therapy.

The prevalence and psychopathologic features of psychiatric adverse events (PAE) in 517 patients taking levetiracetam (LEV) were investigated. Fifty-three (10.1%) patients developed PAE. A significant association was found with previous psychiatric history, history of febrile convulsions, and history of status epilepticus, whereas lamotrigine co-therapy had a protective effect. PAE were not related to the titration schedule of LEV, and certain patients seem to be biologically more vulnerable.

Psychopathological profile in patients with severe bilateral hippocampal atrophy and temporal lobe epilepsy: evidence in support of the Geschwind syndrome?

Bilateral symmetrical hippocampal atrophy (BHA) has been implicated as a possible causal element in various neuropsychiatric disorders, in particular depressive disorder and schizophrenia. To test the hypothesis that bilateral symmetrical severe volume loss of the hippocampi is of causal relevance to these psychiatric syndromes rather than an epiphenomenon we assessed the psychopathology in a group of patients with temporal lobe epilepsy (TLE) and very severe bilateral symmetrical hippocampal atrophy and compared it with that of a patient control group. Patients with TLE and hippocampal volumes smaller than three standard deviations below the mean of a control population were identified and compared with a matched patient population with normal hippocampal volumes. Psychopathology was assessed by blinded trained psychiatrists using the Present State Examination and Neurobehavioral Inventory. The prevalence of psychiatric syndromes was high in both patient groups; however, there was no significant difference between the two groups. With use of the more specific Neurobehavioral Inventory a psychopathological pattern reminiscent of the Geschwind syndrome emerged when patients with BHA were characterized by caregivers. While BHA does not result in an increased prevalence of specific psychiatric syndromes, specific symptoms that characterize the Geschwind syndrome like hypergraphia and hyposexuality might be pathogenically related to hippocampal atrophy.

Repetitive transcranial magnetic stimulation for Tourette syndrome.

In a single-blinded, placebo-controlled, crossover repetitive transcranial magnetic stimulation (rTMS) trial, 16 patients with Gilles de la Tourette syndrome (GTS) received in random sequence 1 Hz motor, premotor, and sham rTMS, which each consisted of two 20-minute rTMS sessions applied on 2 consecutive days. In the 12 patients who completed the trial, there was no significant improvement of symptoms after any of the rTMS conditions as assessed with the Motor tic, Obsessions and compulsions, Vocal tic Evaluation Survey.

Epilepsy, psychosis and clozapine.

Six patients with epilepsy and severe psychosis were treated with the atypical antipsychotic clozapine. The use of clozapine might be complicated in epileptic patients because of an increased risk of seizures. However, none of the reported patients had an increase of their seizure frequency, in contrast, three patients had a substantial reduction of seizures. One patient had a reduction of non-epileptic seizures as well. In the second part of this paper, combinations of clozapine with newer and older anticonvulsants as well as their interactions and associated risks are discussed.

Amygdala pathology in psychosis of epilepsy: A magnetic resonance imaging study in patients with temporal lobe epilepsy.

Psychosis of epilepsy (POE) has been recognized as a severe complication of chronic intractable epilepsy for more than a century. Most of the clinical symptoms of POE are reminiscent of schizophrenia. Nevertheless, there is general agreement that the phenomenology of POE differs from classical schizophrenia. The temporal lobe hypothesis of schizophrenia put forward in the 1960s notes that episodes with paranoid psychoses are more prevalent in temporal lobe epilepsy (TLE). However, the aetiology and pathogenesis of POE are poorly understood. One of the strongest biological findings in schizophrenia is volume loss of temporal lobe structures and the hippocampus in particular. In order to test the hypothesis that atrophy of the hippocampus and the amygdala is found in patients with TLE and POE, we performed a retrospective study of all patients with TLE who were admitted to the assessment unit of the Chalfont Centre for Epilepsy from 1995 until 1999. Twenty-six (2.6%) of these 1008 patients fulfilled inclusion criteria and were compared with 24 patients with TLE without psychopathology and 20 healthy volunteers. All patients underwent extensive MRI investigations, including volumetric data sets and quantitative T(2 )relaxometry. We found that patients with TLE and POE differed from patients with TLE alone and healthy volunteers in that the total brain volumes were significantly smaller. While there were no differences in hippocampal volumes between the three study groups, there was a significant 16-18% enlargement of the amygdala on both sides in patients with POE. Our findings support the notion that POE is a distinct nosologic entity differing from schizophrenia not only in clinical details but also in neurobiological aspects. The finding of amygdala enlargement agrees with the observation of an association between dysphoric disorders of epilepsy and POE described nearly 100 years ago.