Isolated epileptiform activity in children and adolescents: prevalence, relevance, and implications for treatment.

In the field of psychiatry diagnoses are primarily based on the report of symptoms from either the patient, parents, or both, and a psychiatrist's observations. A psychiatric diagnosis is currently the most widely used basis for medication selection and the brain is seldom investigated directly as a source of those symptoms. This study addresses the request from the National Institute of Mental Health (NIMH) Research Domain Criteria Project (RDoC) for scientific research into neurological abnormalities that can be linked to psychiatric symptoms for the purpose of predicting medication response. One such neurological abnormality that has been the focus of many studies over the last three decades is isolated epileptiform discharges (IEDs) in children and adolescents without seizures. We conducted a systematic review of the literature to determine prevalence rates of IEDs within diagnostic categories. We then compared the prevalence of IEDs in the selected literature to our IRB-approved data archive. Our study found a consistent high prevalence of IEDs specifically for ADHD (majority > 25%) and ASD (majority > 59%), and consistent low prevalence rates were found for Depression (3%). If children and adolescents have failed multiple medication attempts, and more than one-third of them have IEDs, then an EEG would be justified within the RDoC paradigm.

Diagnostic Utility of Sodium Lactate Infusion and CO2-35% Inhalation for Panic Disorder.

Laboratory measures have played an integral role in diagnosing pathology; however, compared to traditional medicine, psychiatric medicine has lagged behind in using such measures. A growing body of literature has begun to examine the viability and development of different laboratory measures in order to diagnose psychopathologies. The present review examines the current state of development of both sodium lactate infusion and CO2-35% inhalation as potential ancillary measures to diagnose panic disorder (PD). A previously established 3-step approach to identifying laboratory-based diagnostic tests was applied to available literature assessing the ability of both sodium lactate infusion or CO2-35% inhalation to induce panic attacks in PD patients, healthy controls, and individuals with other psychiatric conditions. Results suggest that across the literature reviewed, individuals with PD were more likely to exhibit panic attacks following administration of sodium lactate or CO2-35% compared to control participants. The majority of the studies examined only compared individuals with PD to healthy controls, suggesting that these ancillary measures are underdeveloped. In order to further determine the utility of these ancillary measures, research is needed to determine if panic attacks following administration of these chemical agents are unique to PD, or if individuals with related pathologies also respond, which may be indicative of transdiagnostic characteristics found across disorders.

Electroencephalogram (EEG) for children with autism spectrum disorder: evidential considerations for routine screening.

Routine electroencephalograms (EEG) are not recommended as a screen for epileptic discharges (EDs) in current practice guidelines for children with autism spectrum disorder (ASD). However, a review of the research from the last three decades suggests that this practice should be reevaluated. The significant comorbidity between epilepsy and ASD, its shared biological pathways, risk for developmental regression, and cognitive challenges demand increased clinical investigation requiring a proactive approach. This review highlights and explains the need for screening EEGs for children with ASD. EEG would assist in differentiating EDs from core features of ASD and could be included in a comprehensive assessment. EEG also meets the demand for evidence-based precision medicine and focused care for the individual, especially when overlapping processes of development are present.

The forsaking of the clinical EEG by psychiatry: how justified?

Despite decades of publications attesting to the role of the clinical EEG in diagnosing and managing psychiatric disorders, the procedure remains highly underutilized in the practice of psychiatry. The visually inspected EEG (vEEG) can detect various forms of abnormalities, each with its own clinical significance. Abnormalities can be paroxysmal (i.e., suggestive of an epileptic-like process) or stationary. The most important unanswered question remains the value of detecting epileptiform activity in a nonepileptic psychiatric patient in predicting favorable responses to anticonvulsant treatment. Despite the many shortcomings of vEEG, the available evidence suggests that in the presence of paroxysmal activity in a nonepileptic psychiatric patient a trial of a psychotropic anticonvulsant may be warranted if standard treatment has failed. More research on the contribution of paroxysmal EEG abnormalities to the problem of episodic psychiatric symptoms (e.g., panic attacks, dissociative episodes, repeated violence) is sorely needed. It is postulated that at least some of these conditions may represent an epilepsy spectrum disorder. Similarly, the significance of the presence of a slow-wave activity (whether focal or generalized) also deserves further well-designed research to ascertain the exact clinical significance. Nonetheless, the available data suggest that further medical workup is necessary to ascertain the nature and degree of the pathology when present.

Relationships of behavioral measures of frontal lobe dysfunction with underlying electrophysiology in cocaine-dependent patients.

BACKGROUND AND OBJECTIVES: Despite evidence that frontal lobe functioning is impaired in cocaine-dependent individuals, relationships between behavioral measures of frontal dysfunction and electrophysiological measures of inhibition in cocaine use have not been explored. METHODS: Using the Frontal Systems Behavior Scale (FrSBe), frontal dysfunction was assessed in a group of abstinent cocaine-dependent subjects (N = 49) and healthy controls (N = 32). Using transcranial magnetic stimulation (TMS) and evoked potential (EP)-based electrophysiological measures of inhibition, we assessed associations between these measures and FrSBe estimates of frontal dysfunction. RESULTS: Patients had significantly higher FrSBe scores for executive dysfunction, disinhibition, and apathy than controls. Lower TMS-based resting motor thresholds (ie, hyperexcitability) were significantly associated with higher executive dysfunction scores in the patients. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: Relationships between FrSBe scores and TMS-based measures highlight neurophysiological aberrations underlying frontal lobe dysfunction in cocaine abusers. TMS and EP measures may be useful probes of the intermediary steps between frontal lobe dysfunction and addictive behavior.

What does the electroencephalogram tell us about the mechanisms of action of ECT in major depressive disorders?

Electroconvulsive therapy (ECT) remains to be one of the most effective treatment options in treatment-resistant major depressive disorder (MDD). From the early days, researchers have embarked on extracting information from electroencephalography (EEG) recordings before, during, and after ECT to identify neurophysiological targets of ECT and discover EEG predictors of response to ECT in patients with MDD. In this article, we provide an overview of visually detected and quantitative EEG features that could help in furthering our understanding of the mechanisms of action of ECT in MDD. We further discuss the EEG findings in the context of postulated hypotheses of ECT therapeutic pathways. We introduce an alternative and unifying hypothesis suggesting that ECT may exert its therapeutic efficacy through resetting the aberrant functional connectivity and promoting the generation of new and healthy connections in brain regions implicated in MDD pathophysiology, a mechanism that may be in part mediated by the ECT-induced activation of inhibitory and neuroplasticity mechanisms. We further discuss the added value of EEG markers in the larger context of ECT research and as complementary to neuroimaging and genetic markers. We conclude by drawing attention to the need for longitudinal studies in large cohort of patients and the need for standardization and validation of EEG algorithms of functional connectivity across studies to facilitate the translation of EEG correlates of ECT response in routine clinical practice.

Anticonvulsant medications for panic disorder: a review and synthesis of the evidence.

OBJECTIVES: Currently, there are no guidelines for when to use an antiepileptic drug (AED) in nonepileptic panic disorder (PD) patients. We conducted this review to ascertain what guidance available literature can provide as to when to consider AEDs for PD patients. METHODS: The primary data sources were PubMed and Google-Scholars. Search was limited to "English" and "Humans". Only papers addressing use of nonbenzodiazepine AEDs in PD were included. Data regarding study subjects, the AED utilized, and clinical responses were collected. EEG data were used to classify reports of patients with abnormal versus those with normal and/or no EEG work-up. RESULTS: Ten reports were identified for use of AEDs in PD patients with abnormal EEGs with a total of 20 patients (17 responders). None of the 10 reports were controlled studies. Eighteen reports were identified for use of AEDs in panic patients with either normal EEGs or unselected groups (no EEG work-up). Out of the 18 reports, three were controlled studies. Included in the 18 studies were 253 patients (137 responders). CONCLUSIONS: We preliminary concluded that EEG work-up could be useful in guiding the treatment in PD as an abnormal EEG may be indicative of a higher likelihood of a positive response to an AED.

Electrical, molecular and behavioral effects of interictal spiking in the rat.

OBJECTIVE: Epilepsy is a disease characterized by chronic seizures, but is associated with significant comorbidities between seizures including cognitive impairments, hyperactivity, and depression. To study this interictal state, we characterized the electrical, molecular, and behavior effects of chronic, neocortical interictal spiking in rats. METHODS: A single injection of tetanus toxin into somatosensory cortex generated chronic interictal spiking measured by long-term video EEG monitoring and was correlated with motor activity. The cortical pattern of biomarker activation and the effects of blocking MAPK signaling on interictal spiking and behavior were determined. RESULTS: Interictal spiking in this model increases in frequency, size, and becomes repetitive over time, but is rarely associated with seizures. Interictal spiking was sufficient to produce the same molecular and cellular pattern of layer 2/3-specific CREB activation and plasticity gene induction as is seen in the human interictal state. Increasing spike frequency was associated with hyperactivity, demonstrated by increased ambulatory activity and preferential circling toward the spiking hemisphere. Loud noises induced epileptic discharges, identical to spontaneous discharges. Treatment with a selective MAPK inhibitor prevented layer 2/3 CREB activation, reduced the frequency of epileptic discharges, and normalized behavioral abnormalities, but had no effect on seizures induced by electrical kindling. INTERPRETATION: These results provide insights into the development of interictal epileptic spiking, their relationship to behavior, and suggest that interictal and ictal activities utilize distinct molecular pathways. This model, that parallels recent observations in humans, will be useful to develop therapeutics against interictal spiking and its behavioral comorbidities.

Correlation between early subjective response to antipsychotics and the number of hospitalizations and hospitalization days in a period of 10-11 years in schizophrenia patients.

INTRODUCTION: Research into the significance of early subjective response to antipsychotic medication has so far only involved observation periods of up to 1 year. METHOD: The Drug Attitude Inventory (DAI-10) questionnaires, completed by patients with the diagnosis of schizophrenia in 1997-1998, were the bases for this study. In 2009, data on 36 patients (18 women and 18 men) with 10-11 years of follow-up information were found whose completed DAI questionnaires were on record in the hospital register. The data included the number of hospitalizations, which enabled to calculate the total number of days spent in hospital for each patient. Statistical analysis examined possible correlations between the DAI scale results and the number of hospitalizations in 1997/1998-2009 and the number of days spent in the hospital during that period of time. RESULTS: The total number of hospitalizations in the period of 11-12 years has shown no correlations with the results of the DAI-10 scale (p = 0.23). However, the number of days spent in hospital in the period of observation has shown a reverse correlation between the results of the DAI-10 scale in 1997-1998 and the number of days spent in hospital (p = 0.037). The higher the result of the DAI-10 scale was in 1997-1998 (indicating the absence of a dysphoric response to antipsychotic medications), the fewer days of hospitalization were found in the researched period. CONCLUSIONS: Early subjective response to antipsychotic drugs shows a relation to the number of days spent in hospital in the period of observation over 10 years. The data suggest that an early dysphoric response to antipsychotic medications is associated with more days spent in the hospital during subsequent years.

Relevance of attention in auditory sensory gating paradigms in schizophrenia A pilot study.

The paired-click paradigm (PCP) is widely used to study sensory habituation or gating in a number of psychiatric and neurological conditions. The classic paradigm does not control for attentional factors. In order to assess the influences of incorporating attentional control measures we administered the auditory PCP (S1-S2) in three different attention (passive, auditory attention to S2, visual attention to a concurrent continuous performance task [CPT]) conditions to a group of chronic, medicated schizophrenia patients (N=12) and a group of healthy subjects (N=15) to evaluate the effects of attention on sensory gating measures. A significant effect of attention on S1 amplitudes was shown for P50 in both groups, and N100 or P200 in schizophrenia patients. Attention status had a significant effect on S2 amplitudes for N100 and P200, and N100 and P200 gating ratios. Despite the effect of attention on S1 P50 amplitudes there was no effect on the gating ratio. In terms of group differences, visual attention to the concurrent CPT during the paired-click sensory gating task significantly enhanced the detection of deficient gating of the N100 and P200 components in schizophrenia patients. The data support the continued utilization of the passive gating paradigm for examining P50 gating but strongly suggest that for studies examining gating of the N100 or P200 components, a visual distraction paradigm may enhance the detection of abnormal gating in schizophrenia patients.

Dissociative symptoms and interregional EEG cross-correlations in paranoid schizophrenia.

Recent findings indicate that binding and synchronization of distributed activities are crucial for the mechanism of consciousness, and there is increased evidence that disruptions in feature binding produce disintegration of consciousness in schizophrenia. These data suggest that the disrupted binding and disintegration of consciousness could be related to dissociation, which is historically linked to Bleuler's concept of splitting in schizophrenia. In the present study we aimed to investigate relations among electroencephalogram (EEG) activities of cortical sites and used psychometric measures of positive and negative schizophrenia symptoms (Positive and Negative Syndrome Scale) and the Dissociative Experiences Scale (DES) in 58 patients with paranoid schizophrenia. The results show statistically significant Spearman correlations of the DES with cross-correlation function in nine (of 16) EEG pairs. Positive symptoms display significant Spearman correlation with mean of cross-correlation function in only one EEG pair (F4-C4). Results of the Mann-Whitney test between patients with higher (DES > or = 30) and lower dissociation show statistically significant differences between the groups for cross-correlations in nine EEG pairs. The results of this study provide the first supportive evidence for a negative relationship between cross-correlation indices and symptoms of dissociation in schizophrenia.

Deficit Versus Nondeficit Schizophrenia: An MEG-EEG Investigation of Resting State and Source Coherence-Preliminary Data.

This study investigated the magneto- and electroencephalography (MEG and EEG, respectively) resting state to identify the deviations closely associated with the deficit syndrome (DS) in schizophrenia patients. Ten subjects in each group (control, DS, and nondeficit schizophrenia [NDS]) were included. Subjects underwent MEG-EEG recordings during a resting state condition. MEG coherence source imaging (CSI) in source space and spectral analysis in sensor space were performed. Significant differences were found between the 2 patient groups: (1) MEG and EEG spectral analysis showed significantly higher power at low frequencies (delta band) at sensor space in DS compared with NDS patients; (2) source analysis revealed larger power in the DS compared with NDS group at low frequencies in the frontal region; (3) NDS patients showed significantly higher MEG signal relative power in beta bands in sensor space compared with DS patients; (4) both DS and NDS patients showed higher EEG absolute power at higher beta band compared to controls; and (5) patients with DS were found to have a significantly higher MEG CSI than controls in the beta frequency band. These data support the observation of increased power in the low-frequency EEG/MEG rhythms associated with the DS. Increased power in the beta rhythms was more associated with the NDS.

Sensory gating in intracranial recordings--the role of phase locking.

For patients with schizophrenia, a deficient gating (or filtering) of sensory input has been described. One major approach to study this sensory gating is to measure event-related potentials (ERPs) in response to paired clicks. In these experiments, sensory gating is quantified as amplitude reduction of the ERP components P50 and N100 from the 1st to the 2nd stimulus. In ERP studies brain electrical signals are averaged over single trials. Alterations in phase locking might be one factor contributing to the observed deficits in sensory gating, but findings have been inconclusive as yet. In particular, the contribution of different frequency bands to the deficit required further investigation. We studied N100 gating by intracranial recordings in a sample of epilepsy patients and subdivided the group into good and poor gators of the intracranial ERP component N100. Data were evaluated by frequency specific wavelet-based phase and power analyses. Poor N100 gators had an increased phase locking in the frequency range from 6.0-15.1 Hz after the 2nd stimulus, as compared to good gators. Other group differences were apparent already before the 2nd stimulus. Poor gators had less phase locked beta band activity (20.2-30.0 Hz) than good gators 200-315 ms after the onset of the 1st stimulus. Within the group of poor gators, lower values of phase locking in this frequency range were also associated with lower gating ratios. The reduced beta band response in response to the 1st stimulus may reflect poorer memory encoding of the 1st stimulus in poor gators. This in turn might lead to increased demands to process the 2nd stimulus.

Reduction of prelimbic inhibitory gating of auditory evoked potentials after fear conditioning.

Inhibitory gating (IG) is a basic central nervous system process for filtering repetitive sensory information. Although IG deficits coincide with cognitive and emotional dysfunction in a variety of neuropsychiatric disorders, limited research has been completed on the basic, functional nature of IG. Persistent IG occurs in rat prelimbic medial prefrontal cortex (mPFC), a crucial site for modulating emotional learning. To investigate the interaction of affect and IG, we recorded local field potentials (LFP) directly from prelimbic mPFC and examined the influence of tone-shock fear conditioning (FC) on IG. Behavioral reactions during IG were observed before and after FC, and increase of orienting response after FC indicated induction of tone-shock association. After FC, some components of LFP response exhibited short-term weakening of IG. On a subsequent day of recording, IG strengthened for all LFP components, but individual components differed in their particular changes. Affective regulation of IG represents an important factor influencing within-subject IG variability, and these results have implications for understanding the role of rapid, implicit neural coding involved in emotional learning and affective disruption in psychiatric disease.

Evoked potential variability.

An unsupervised correlation-based clustering method was developed to assess the trial-to-trial variability of auditory evoked potentials (AEPs). The method first decomposes single trials into three frequency bands, each containing activity primarily associated with one of the three major AEP components, i.e., P50, N100 and P200. Next, single-trial evoked potentials with similar post-stimulus characteristics are clustered and selectively averaged to determine the presence or absence of an AEP component. The method was evaluated on actual AEP and spontaneous EEG data collected from 25 healthy participants using a paradigm in which pairs of identical tones were presented, with the first stimulus (S1) presented 0.5s before the second stimulus (S2). Homogeneous, well-separated clusters were obtained and substantial AEP variability was found. Also, there was a trend for S2 to produce fewer 'complete' (and significantly smaller) responses than S1. Tests conducted on spontaneous EEG produced similar clusters as obtained from EP data, but significantly fewer stimuli produced responses containing all three EP components than seen in AEP data. These findings suggest that the clustering method presented here performs adequately to assess trial-to-trial EP variability. Also, the results suggest that the sensory gating observed in normal controls may be caused by the fact that the second stimulus generates fewer 'responsive' trials than the first stimulus, thus resulting in smaller ensemble averages.

A pilot study revealing impaired P50 gating in antisocial personality disorder.

The authors investigated preattentive filtering assessed by P50 gating in nine participants with antisocial personality disorder (ASPD) and seven with adult-onset antisocial behavior (AAB). Relative to 15 comparison subjects, gating was impaired in ASPD, suggesting abnormal pre-attentive filtering in pathological impulsivity.

Translating biological parameters into clinically useful diagnostic tests.

Psychiatry has lagged behind other specialties in developing diagnostic laboratory tests for the purpose of confirming or ruling out a diagnosis. Biological research into the pathophysiology of psychiatric disorders has, however, yielded some highly replicable abnormalities that have the potential for development into clinically useful diagnostic tests. To achieve this goal, a process for systematic translation must be developed and implemented. Building on our previous work, we review a proposed process using four clearly defined steps. We conclude that biological parameters currently face challenges in their pathways to becoming diagnostic tests because of both the premature release and premature abandonment of tests. Attention to a systematic translation process aided by these principles may help to avoid these problems.

Diminished P50, N100 and P200 auditory sensory gating in bipolar I disorder.

Bipolar I disorder is associated with diminished gating of the auditory evoked P50 component. P50 gating may relate to early filtering of sensory information, protecting higher-order cognitive functions. Gating of the auditory evoked N100 and P200 components has not been investigated in bipolar I disorder, although N100 and P200 gating could reflect different mechanisms and functions in the process of filtering sensory information in addition to those reflected by P50 gating. We investigated P50, N100, and P200 gating assessed with the paired-click paradigm in 22 subjects with bipolar I disorder and 54 healthy controls. Peak amplitudes and latencies were assessed at Cz for the P50, N100, and P200 components. Gating was defined as the reduction in peak amplitude from the first (S1) to the second stimulus (S2) of a stimulus pair, and expressed as gating ratio ([S2(amplitude)/S1(amplitude)]()100) and difference score (S1(amplitude)-S2(amplitude)). Group differences were detected with multivariate analyses and controlled for differences in age and ethnicity. Subjects with bipolar I disorder had higher P50, N100 and P200 ratios and lower difference scores compared with findings for controls. These findings extend the existing evidence on impaired sensory gating in bipolar I disorder beyond the P50, suggesting impaired filtering at both pre-attentive and early attentive levels in bipolar I disorder.

The Role of Age, Gender, Education, and Intelligence in P50, N100, and P200 Auditory Sensory Gating.

P50, N100, and P200 auditory sensory gating reflect distinct mechanisms involved in protecting the integrity of higher-order functions. They have been implicated in multiple psychiatric disorders. Recent studies showed the (limited) effects of age and gender on sensory gating in control subjects, suggesting there may be other sources of variance. Two potential sources may be education and intelligence (intellectual capability), variables that frequently differ across studies and across experimental groups. We explored potential effects of age, gender, education, and intelligence (Shipley intelligence scale) on P50, N100, and P200 sensory gating measured with the paired-click paradigm in 60 healthy subjects recruited from the general population. Increased intellectual capability related to stronger N100 and P200 gating and more pronounced N100 and P200 amplitudes. In addition, increased age related to weaker P200 gating and smaller P200 amplitudes. Gender had negligible effects. Intellectual capability or age could contribute to variation in N100 or P200 auditory sensory gating and should be controlled for when studying sensory gating in clinical and control groups.

Evoked Potentials Investigations of Deficit Versus Nondeficit Schizophrenia: EEG-MEG Preliminary Data.

Heterogeneity of schizophrenia is a major obstacle toward understanding the disorder. One likely subtype is the deficit syndrome (DS) where patients suffer from predominantly negative symptoms. This study investigated the evoked responses and the evoked magnetic fields to identify the neurophysiological deviations associated with the DS. Ten subjects were recruited for each group (Control, DS, and Nondeficit schizophrenia [NDS]). Subjects underwent magnetoencephalography (MEG) and electroencephalography (EEG) testing while listening to an oddball paradigm to generate the P300 as well as a paired click paradigm to generate the mid-latency auditory-evoked responses (MLAER) in a sensory gating paradigm. MEG-coherence source imaging (CSI) during P300 task revealed a significantly higher average coherence value in DS than NDS subjects in the gamma band (30-80 Hz), when listening to standard stimuli but only NDS subjects had a higher average coherence level in the gamma band than controls when listening to the novel sounds. P50, N100, and P3a ERP amplitudes (EEG analysis) were significantly decreased in NDS compared with DS subjects. The data suggest that the deviations in the 2 patient groups are qualitatively different. Deviances in NDS patients suggest difficulty in both early (as in the gating paradigm), as well as later top-down processes (P300 paradigm). The main deviation in the DS group was an exaggerated responsiveness to ongoing irrelevant stimuli detected by EEG whereas NDS subjects had an exaggerated response to novelty.