Normalization of EEG in depression after antidepressant treatment with sertraline? A preliminary report.

BACKGROUND: MDD patients with abnormal EEG patterns seem more likely to be non-responsive to the antidepressants escitalopram and venlafaxine, but not sertraline, than patients without EEG abnormalities. This finding suggests that patients with both MDD and abnormal EEGs may differentially respond to antidepressant treatment. In the current study, we investigated whether depressed patients with an abnormal EEG show a normalization of the EEG related to antidepressant treatment and response and whether such effect is drug specific, and whether having had early life stress (ELS) increases the chance of abnormal activity. METHODS: Baseline and week 8 EEGs and depression symptoms were extracted from a large multicenter study (iSPOT-D, n = 1008) where depressed patients were randomized to escitalopram, sertraline, or venlafaxine-XR treatment. We calculated Odds Ratios of EEG normalization and depression response in patients with an abnormal EEG at baseline, comparing sertraline versus other antidepressants. RESULTS: Fifty seven patients with abnormal EEGs were included. EEGs did not normalize significantly more with sertraline compared to other antidepressants (OR = 1.9, p = .280). However, patients with a normalized EEG taking sertraline were 5.2 times more likely to respond than subjects taking other antidepressants (p = .019). ELS was not significantly related to abnormal activity. LIMITATIONS: Neurophysiological recordings were limited in time (two times 2-minute EEGs) and statistical power (n = 57 abnormal EEGs). CONCLUSIONS: Response rates in patients with normalized EEG taking sertraline were significantly larger than in subjects treated with escitalopram/venlafaxine. This adds to personalized medicine and suggests a possible drug repurposing for sertraline.

The status of sleep abnormalities as a diagnostic test for major depressive disorder.

BACKGROUND: Psychiatry lags other fields in development of diagnostic tests. METHODS: A literature review and meta-analysis was conducted to ascertain if polysomnographic abnormalities (REM density, REM latency, sleep efficiency, slow wave sleep, stage 1 and stage 2 sleep) warrant additional effort to develop them into a clinical diagnostic test for major depressive disorder (MDD). The 31 publications meeting inclusion criteria were then classified into one of three progressive steps using guidelines for evaluating the clinical usefulness of a diagnostic test. RESULTS: Most of the abnormalities found in MDD patients, when compared to healthy controls, occurred in the expected direction with moderate effect sizes but with substantial publication bias and heterogeneity. Eleven studies compared abnormalities in MDD to other psychiatric disorders (step 2a), and four studies provided data on the sensitivity or specificity of the findings in differentiating among the psychiatric disorders that frequently appear on the same differential diagnostic list as MDD (step 2b). No multicenter trial has been conducted prospectively to test the clinical utility of the diagnostic test (step 3). LIMITATIONS: Only published articles in the English language were used. CONCLUSIONS: Sleep studies for the detection of MDD appear replicable with a moderate effect size. However, additional step 1 studies are needed to define the sensitivity and specificity. The heterogeneity of sleep recording, scoring techniques, and MDD must also be addressed.

Standard EEG and the difficult-to-assess mental status.

BACKGROUND: Delirium commonly appears on the differential diagnostic list of psychiatric patients in acute care settings. When a patient is unable or unwilling to answer questions about orientation, determination of possible delirium or other probable etiologies becomes difficult. The role of the standard electroencephalogram (SEEG) in evaluating such patients is not known. METHODS: Exhaustive MEDLINE and PsycInfo searches were performed for the period 1950-2007 for all articles cross-referenced for "delirium" and "EEG." The focus was on method, comorbid conditions, demographics, and prevalence and nature of reported abnormalities. RESULTS: We reviewed a total of 45 articles, of which 12 met criteria for more stringent review. All findings are presented in chronological order. Our analysis focuses on SEEG, although we also allude to quantitative EEG when described. CONCLUSIONS: Diffuse slowing of the EEG is considered one of the hallmarks of an encephalopathic process and is commonly reported in psychiatric patients. The EEG may be helpful in the diagnostic evaluation of patients with a difficult-to-assess mental status.

Sensory gating in the human hippocampal and rhinal regions: regional differences.

To further explore the roles of medial temporal structures in mediating sensory gating of incoming irrelevant or redundant auditory input, twenty-seven patients with intractable epilepsy with depth electrodes implanted in the medial temporal lobe for presurgery evaluation underwent evoked response recording to auditory paired-stimuli (S1-S2). Seventeen subjects were diagnosed with left medial temporal lobe epilepsy (MTLE) and 10 with right MTLE. Only data from the nonlesion side were included. Twenty-three records from rhinal and anterior hippocampal regions, and 21 from posterior hippocampal regions were included in the analysis. The rhinal region had two prominent components (a negativity peaking around 200 ms followed by a positivity peaking around 400 ms). Both the anterior and posterior hippocampal regions exhibited a dominant negative potential peaking around 400 ms. These components were all composed predominantly of slower frequencies. In contrast, a negativity in the posterior hippocampus at around 100 ms was composed of slow and fast frequencies. All components but the early rhinal negativity were attenuated by stimulus repetition. This is the first report documenting that different regions of the medial temporal area are differentially involved in the processing of auditory input, most likely reflecting separate steps of processing. The data support the need for further exploration of the contribution of these regions to sensory gating. This information helps to increase our understanding of this basic but important and complex function.

A four-step approach for developing diagnostic tests in psychiatry.

A four-step approach for developing diagnostic tests in psychiatry is proposed. Step 1, a biological variable is observed to be deviant from healthy controls in a particular patient population. The demonstration of test retest reliability of the finding using blinding procedures is an essential component of this early step. Step 2, is the demonstration of potential clinical usefulness of the specific finding. The two most important objectives at this step are demonstration of difference between the target patient population and appropriate control groups (these should be groups of patients with diagnoses that commonly appear on the differential diagnostic lists of the target disorder). Estimation of the effect size of the finding could be a reasonable guide to which findings should be considered good candidates for Step 3 studies. During Step 3 the performance characteristics of the test should be established. Specifically, the sensitivity, specificity, positive and negative predictive values of the biological marker should be examined. Step 4 defines the clinical application of the test and helps standardize the technique used in large and multicenter clinical trials. Multicenter trials should pave the road towards standardization of laboratory procedures used to conduct the test, as well as providing data regarding cost effectiveness and impact on both short-term and long-term clinical outcomes.

Sensory gating of auditory evoked and induced gamma band activity in intracranial recordings.

Oscillatory activity in the gamma band range (30-50 Hz) and its functional relation to auditory evoked potentials (AEPs) is yet poorly understood. In the current study, we capitalized on the advantage of intracranial recordings and studied gamma band activity (GBA) in an auditory sensory gating experiment. Recordings were obtained from the lateral surface of the temporal lobe in 34 epileptic patients undergoing presurgical evaluation. Two kinds of activity were differentiated: evoked (phase locked) and induced (not phase locked) GBA. In 18 patients, an intracranial P50 was observed. At electrodes with maximal P50, evoked GBA occurred with a similar peak latency as the P50. However, the intensities of P50 and evoked GBA were only modestly correlated, suggesting that the intracranial P50 does not represent a subset of evoked GBA. The peak frequency of the intracranial evoked GBA was on average relatively low (approximately 25 Hz) and is, therefore, probably not equivalent to extracranially recorded GBA which has normally a peak frequency of approximately 40 Hz. Induced GBA was detected in 10 subjects, nearly exclusively in the region of the superior temporal lobe. The induced GBA was increased after stimulation for several hundred milliseconds and encompassed frequencies up to 200 Hz. Single-trial analysis revealed that induced GBA occurred in relatively short bursts (mostly <<100 ms), indicating that the duration of the induced GBA in the averages originates from summation effects. Both types of gamma band activity showed a clear attenuation with stimulus repetition.

Sensory gating in the human hippocampal and rhinal regions.

OBJECTIVE: The objective of this work was to ascertain if sensory gating can be demonstrated within the human medial temporal lobe. METHODS: Eight patients with intractable epilepsy with depth electrodes implanted in the medial temporal lobe for pre-surgery evaluation underwent evoked response recording to auditory paired-stimuli (S1-S2). Each of the eight subjects had a diagnosis of left medial temporal lobe epilepsy (MTLE). RESULTS: Data from the non-focal right hippocampi revealed a large negative response on S1 (starting at about 190 ms and lasting for approximately 300 ms from stimulus onset). Rhinal region recordings revealed a positive response (starting at about 240 ms with a rapid incline, followed by a long-lasting decline). A significant attenuation of both responses to S2 stimuli was observed. CONCLUSIONS: Data are suggestive of an involvement of the human medial temporal lobe in the processing of simple auditory information which occurs in a time frame later than the neocortical auditory evoked components. The exact role of these anatomical structures in the sensory gating process remains to be defined. SIGNIFICANCE: This study provides the first evidence of an activation of the rhinal cortex after simple auditory stimulation and provides new evidence that the activation of the medial temporal lobe structures occurs at a later stage than that of the neocortex.

Effect of tryptophan depletion on alcohol cue-induced craving in abstinent alcoholic patients.

BACKGROUND: The capacity of alcohol cues to precipitate the desire to drink may be an important determinant of relapse to alcohol use in recovering alcohol-dependent patients. This study evaluated whether attenuation of serotonin synthesis via depletion of its precursor tryptophan reduces the magnitude of cue-induced craving for alcohol in recently abstinent alcoholic individuals. METHODS: Alcohol-dependent patients (n = 16), 1 to 3 months after detoxification, who exhibited a 20% or greater increase in reported craving when presented with an alcoholic beverage, completed two additional alcohol cue-exposure test days, 1 week apart. Each cue exposure was preceded by administration of a concentrated amino acid drink that resulted in a rapid and significant decline in plasma free tryptophan (active depletion, no tryptophan supplementation) or a similar drink containing tryptophan (placebo depletion). Tests were conducted in a randomized, double-blind fashion. RESULTS: There were no significant changes in the magnitude of cue-induced craving with active tryptophan depletion compared with placebo. CONCLUSIONS: These data question the dependence of alcohol cue-induced craving in sober alcoholics on the ongoing synthesis of serotonin.

EEG monitoring in depressed patients undergoing repetitive transcranial magnetic stimulation.

To date, 33 subjects diagnosed with major depressive disorder have undergone transcranial magnetic stimulation (TMS) in the authors' clinic. Five of these patients showed minimal electroencephalogram (EEG) variants at baseline. The authors describe the course of treatment and serial EEGs in 3 of the 5 patients who did not show progressive EEG changes in association with active rTMS. These three cases suggest that minimal EEG anomalies at baseline need not serve as a contraindication to undergoing rTMS. Two patients with progressive EEG changes in association with sham rTMS in one and active rTMS in the other are also discussed.

Auditory verbal hallucinations and dysfunction of the neural substrates of speech.

OBJECTIVE: to evaluate the neural substrate of auditory verbal hallucinations (AVH), the correlation between AVH and subvocal speech (hereafter SVS), and the relationship between speech and AVH. METHOD: we reviewed the papers found by an electronic literature search on hallucinations and speech. The review was extended to the papers cited in these publications and to classical works. RESULTS: there is no conclusive evidence of structural abnormality of the speech perception area in hallucinating schizophrenic patients. However there is evidence of electrophysiological abnormalities of the auditory and speech perception cortices. Functional imaging data are inconsistent, yet point to the left superior temporal gyrus as one of the neural substrates for AVH. There is also evidence that SVS could accompany the experience of AVH. CONCLUSION: there is evidence that dysfunction of brain areas responsible for speech generation is a fundamental mechanism for generating AVH in schizophrenia. It results in a secondary activation of Wernicke's area (speech perception) and Broca's area (speech expression). The first leading to the experience of hallucinations, and the second, eventually, gives rise to a variable degree of vocal muscle activity detectable by EMG, and/or faint vocalizations detectable by sensitive microphones placed at proximity of the larynx. Direct stimulation or disease of Wernicke's area produces AVH without SVS.

Elevated motor threshold in drug-free, cocaine-dependent patients assessed with transcranial magnetic stimulation.

BACKGROUND: Transcranial magnetic stimulation (TMS) provides a noninvasive method of examining cortical inhibitory and excitatory processes and cortical excitability in awake subjects. There is evidence from clinical and electroencephalographic (EEG) data that cortical excitability may be abnormal in some psychiatric populations. Chronic cocaine abuse influences a number of neurotransmitters that are involved in the excitatory/inhibitory balance of the cerebral cortex. This pilot study was conducted to ascertain the possible utility of TMS in examining cortical excitability in a population of chronic cocaine abusers. METHODS: The right and left motor thresholds of ten cocaine-dependent subjects, according to DSM-IV, and ten normal control subjects were examined using single pulse TMS. RESULTS: The resting motor thresholds resulting from stimulation of the right or the left motor cortical regions were significantly elevated in cocaine-dependent subjects compared with matched control subjects. CONCLUSIONS: These pilot data suggest that chronic cocaine use significantly alters cortical excitability in the direction of increased inhibition or decreased excitability. We hypothesize that this observation reflects adaptation to those effects of cocaine intoxication that promote cortical excitability and seizures.

Electroencephalogram and repetitive transcranial magnetic stimulation.

Scalp recordings of the electroencephalogram (EEG) have been used in association with repetitive transcranial magnetic stimulation (rTMS) investigations as a safety measure in monitoring ongoing EEG activity and as a neurophysiologic tool in examining the specific effects induced by the magnetic stimulus on the EEG or evoked potentials (EPs). Medline review on the use of EEG or EPs with rTMS reveals that this area has been largely unexplored. Limited available studies attest to the potential for studies combining EEG/EPs and rTMS to be useful in further elucidating the normal brain physiology. Herein, we report on our experience with continuous EEG sampling combined with rTMS in patients with major depression (n = 14), schizophrenia (n = 7), and obsessive-compulsive disorder (n = 5). Our data support the practice of using continuous EEG monitoring when the stimulation parameters fall outside established safety guidelines.

Transcranial magnetic stimulation and auditory hallucinations in schizophrenia.

12 patients with schizophrenia and auditory hallucinations received 1 Hz transcranial magnetic stimulation of left temporoparietial cortex. In a double-blind crossover trial, active stimulation significantly reduced hallucinations relative to sham stimulation.

A randomized clinical trial of repetitive transcranial magnetic stimulation in the treatment of major depression.

BACKGROUND: Multiple groups have reported on the use of repetitive transcranial magnetic stimulation (rTMS) in treatment-resistant major depression. The purpose of this study is to assess the efficacy of rTMS in unmedicated, treatment-resistant patients who meet criteria for major depression. METHODS: Depressed subjects, who had failed to respond to a median of four treatment trials, were assigned in a randomized double-blind manner to receive either active (n = 10; 20 2-sec trains of 20 Hz stimulation with 58-sec intervals; delivered at 80% motor threshold with the figure-of-eight coil positioned over the left dorsolateral prefrontal cortex) or sham (n = 10; similar conditions with the coil elevated and angled 45 degrees tangentially to the scalp) rTMS. These sequences were applied during 10 consecutive weekdays. Continuous electroencephalogram sampling and daily motor threshold determinations were also obtained. RESULTS: The group mean 25-item Hamilton Depression Rating Scale (HDRS) score was 37.2 (+/- 2.0 SEM) points. Adjusted mean decreases in HDRS scores were 14.0 (+/- 3.7) and 0.2 (+/- 4.1) points for the active and control groups, respectively (p <.05). One of 10 subjects receiving active treatment demonstrated a robust response (i.e., HDRS decreased from 47 to 7 points); three other patients demonstrated 40-45% decreases in HDRS scores. No patients receiving sham treatment demonstrated partial or full responses. CONCLUSIONS: A 2-week course of active rTMS resulted in statistically significant but clinically modest reductions of depressive symptoms, as compared to sham rTMS in a population characterized by treatment resistance.

Similarities in the disturbances in cortical information processing in alcoholism and aging: a pilot evoked potential study.

OBJECTIVE: To examine the hypothesis that chronic alcohol use causes accelerated aging of the brain. METHODS: The auditory evoked potentials (EPs) were compared in three groups of 10 subjects each: (a) middle-aged individuals meeting DSM-IV criteria for alcohol dependence, (b) age- and gender-matched group of healthy individuals, and (c) an older (>65 years) group of gender-matched healthy individuals. Multiple levels of cortical information processing were examined using EPs. Early stages of information processing, related to sensory gating and stimulus classification (P50, N100/P200), were studied using a paired-click paradigm. Later stages of information processing associated with memory upgrading and identification of novel stimuli (P300) were studied using an oddball paradigm. RESULTS: The amplitude and latency of the P300 of the alcoholic patients and the older healthy subjects differed significantly from those of the younger healthy group. Both groups showed changes that have been reported in association with aging. A tendency towards decreased sensory gating in later stages of information processing was noted in the aged healthy individuals. CONCLUSIONS: These data suggest that alcohol dependence may accelerate the aging process. The tendency towards a sensory gating deficit during the attentive phase of information processing in older healthy subjects requires further investigation because it may be a marker for an increased proneness to developing psychotic symptoms in that group.

Transcranial magnetic stimulation of left temporoparietal cortex in three patients reporting hallucinated "voices".

BACKGROUND: Prior studies suggest that auditory hallucinations of "voices" arise from activation of speech perception areas of the cerebral cortex. Low frequency transcranial magnetic stimulation (TMS) can reduce cortical activation. METHODS: We have studied three schizophrenic patients reporting persistent auditory hallucinations to determine if low frequency TMS could curtail these experiences. One hertz stimulation of left temporoparietal cortex was compared with sham stimulation using a double-blind, cross-over design. RESULTS: All three patients demonstrated greater improvement in hallucination severity following active stimulation compared to sham stimulation. Two of the three patients reported near total cessation of hallucinations for > or = 2 weeks. CONCLUSIONS: TMS may advance our understanding of the mechanism and treatment of auditory hallucinations.

Midlatency evoked potentials attenuation and augmentation reflect different aspects of sensory gating.

A broad definition of sensory gating refers to the ability of the brain to modulate its sensitivity to incoming sensory stimuli. This definition allows the concept of gating to include both the capacities to minimize or stop responding to incoming irrelevant stimuli (gating out) and to respond when a novel stimulus is presented or a change occurs in ongoing stimuli (gating in). In order to further characterize the function of sensory gating, we examined the attenuation (decreased responding) and augmentation (increased responding) of the P50 EP amplitudes in 22 normal volunteers. Three EP paradigms, each including a number of conditions, designed to examine both EP habituation (inhibition) and dishabituation (excitation) were administered to each subject. In conditions designed to examine habituation (identical pairs of clicks or trains of repetitive identical clicks), the P50 behaved, as expected, with decrease of the amplitude with repetition. In conditions designed to examine dishabituation the amplitude of the P50, EP did not decrease as much (and frequently increased) with stimulus change. The results suggest that the P50 EP is sensitive to the effects of stimulus repetition and stimulus change and can be used to study the different aspects of sensory gating.

Comparison of four components of sensory gating in schizophrenia and normal subjects: a preliminary report.

Dysfunction of sensory gating has been implicated in the pathophysiology of schizophrenia. The goal of this study was to provide evidence that sensory gating dysfunction in schizophrenia patients is a compounded problem with difficulty in filtering out irrelevant input and filtering in relevant input at both an early-preattentive stage and a later, early-attentive stage of information processing. Four components of sensory gating were examined in 12 medicated, stable schizophrenia patients and 12 age- and sex-matched normal control subjects. Evoked potential paradigms designed to examine the effects of stimulus repetition and stimulus change were utilized. Attenuation of the amplitude of the P50 and the N100 evoked potentials with stimulus repetition was significantly decreased in schizophrenia patients as compared to normal control subjects. The presentation of deviant stimuli caused the degree of attenuation to decrease in normal subjects. This effect was much decreased (and at times reversed) in schizophrenia subjects. These data suggest that schizophrenia patients have difficulty inhibiting incoming, irrelevant stimuli and responding to incoming, significant input as measured by preattentive EPs (P50). The data also suggest that similar abnormalities can be demonstrated at a slightly later phase of information processing (i.e. early-attentive phase) using the N100 EP.