Daniel M. Alschuler

Current Source Density Measures of Electroencephalographic Alpha Predict Antidepressant Treatment Response

BACKGROUND Despite recent success in pharmacologic treatment of depression, the inability to predict individual treatment response remains a liability. This study replicates and extends findings relating pretreatment electroencephalographic (EEG) alpha to treatment outcomes for serotonergic medications. METHODS Resting EEG (eyes-open and eyes-closed) was recorded from a 67-electrode montage in 41 unmedicated depressed patients and 41 healthy control subjects. Patients were tested before receiving antidepressants including a serotonergic mode of action (selective serotonin reuptake inhibitor [SSRI], serotonin and norepinephrine reuptake inhibitor, or SSRI plus norepinephrine and dopamine reuptake inhibitor). EEG was quantified by frequency principal components analysis of spectra derived from reference-free current source density (CSD) waveforms, which sharpens and simplifies EEG topographies, disentangles them from artifact, and yields measures that more closely represent underlying neuronal current generators. RESULTS Patients who did not respond to treatment had significantly less alpha CSD compared with responders or healthy control subjects, localizable to well-defined posterior generators. The alpha difference between responders and nonresponders was greater for eyes-closed than eyes-open conditions and was present across alpha subbands. A classification criterion based on the median alpha for healthy control subjects showed good positive predictive value (93.3) and specificity (92.3). There was no evidence of differential value for predicting response to an SSRI alone or dual treatment targeting serotonergic plus other monoamine neurotransmitters. CONCLUSIONS Findings confirm the value of EEG alpha amplitude as a viable predictor of antidepressant response and suggest that personalized treatments for depression may be identified using simple electrophysiologic CSD measures.

Identifying electrode bridging from electrical distance distributions: A survey of publicly-available EEG data using a new method

OBJECTIVE EEG topographies may be distorted by electrode bridges, typically caused by electrolyte spreading between adjacent electrodes. We therefore sought to determine the prevalence of electrode bridging and its potential impact on the EEG literature. METHODS Five publicly-available EEG datasets were evaluated for evidence of bridging using a new screening method that employs the temporal variance of pairwise difference waveforms (electrical distance). Distinctive characteristics of electrical distance frequency distributions were used to develop an algorithm to identify electrode bridges in datasets with different montages (22-64 channels) and noise properties. RESULTS The extent of bridging varied substantially across datasets: 54% of EEG recording sessions contained an electrode bridge, and the mean percentage of bridged electrodes in a montage was as high as 18% in one of the datasets. Furthermore, over 40% of the recording channels were bridged in 9 of 203 sessions. These findings were independently validated by visual inspection. CONCLUSIONS The new algorithm conveniently, efficiently, and reliably identified electrode bridges across different datasets and recording conditions. Electrode bridging may constitute a substantial problem for some datasets. SIGNIFICANCE Given the extent of the electrode bridging across datasets, this problem may be more widespread than commonly thought. However, when used as an automatic screening routine, the new algorithm will prevent pitfalls stemming from unrecognized electrode bridges.

Neurocognitive predictors of antidepressant clinical response

BACKGROUND Executive dysfunction and psychomotor slowing in depressed patients have been associated with poor antidepressant clinical response, but little is known about the value of neurocognitive tests for differential prediction of response. METHODS This report presents new findings for 70 depressed patients tested on neurocogntive tests before receiving treatment with a SSRI (escitalopram or citalopram), NDRI (bupropion) or dual mechanism therapy including a serotonergic agent, and for 57 healthy controls. RESULTS As predicted from previous research, patients who did not respond to a SSRI or dual therapy showed poorer word fluency than responders, whereas this was not seen for patients treated with bupropion alone. Longer choice reaction time (RT) was also found in nonresponders to a SSRI or dual therapy, but the opposite trend was seen for bupropion. Using a combined index of word fluency and RT (with normative performance as a cutoff) yielded differential predictions of response. Equal to or above normal performance predicted good response to a SSRI or dual therapy, with high positive predictive value (90%) and specificity (78%) but lower sensitivity (53%). In contrast, less than normal performance predicted good response to bupropion alone (positive predictive value=82%; specificity=67%; sensitivity=90%). LIMITATIONS Relatively small sample size, no placebo control, and combining across SSRI alone and dual treatments. CONCLUSIONS Although findings are preliminary due to small sample size, brief tests of word fluency and psychomotor speed may help identify depressed patients who are unresponsive to a serotonergic agent, but who may respond to bupropion alone.

Auditory event-related potentials and alpha oscillations in the psychosis prodrome: Neuronal generator patterns during a novelty oddball task

Prior research suggests that event-related potentials (ERP) obtained during active and passive auditory paradigms, which have demonstrated abnormal neurocognitive function in schizophrenia, may provide helpful tools in predicting transition to psychosis. In addition to ERP measures, reduced modulations of EEG alpha, reflecting top-down control required to inhibit irrelevant information, have revealed attentional deficits in schizophrenia and its prodromal stage. Employing a three-stimulus novelty oddball task, nose-referenced 48-channel ERPs were recorded from 22 clinical high-risk (CHR) patients and 20 healthy controls detecting target tones (12% probability, 500Hz; button press) among nontargets (76%, 350Hz) and novel sounds (12%). After current source density (CSD) transformation of EEG epochs (-200 to 1000ms), event-related spectral perturbations were obtained for each site up to 30Hz and 800ms after stimulus onset, and simplified by unrestricted time-frequency (TF) principal components analysis (PCA). Alpha event-related desynchronization (ERD) as measured by TF factor 610-9 (spectral peak latency at 610ms and 9Hz; 31.9% variance) was prominent over right posterior regions for targets, and markedly reduced in CHR patients compared to controls, particularly in three patients who later developed psychosis. In contrast, low-frequency event-related synchronization (ERS) distinctly linked to novels (260-1; 16.0%; mid-frontal) and N1 sink across conditions (130-1; 3.4%; centro-temporoparietal) did not differ between groups. Analogous time-domain CSD-ERP measures (temporal PCA), consisting of N1 sink, novelty mismatch negativity (MMN), novelty vertex source, novelty P3, P3b, and frontal response negativity, were robust and closely comparable between groups. Novelty MMN at FCz was, however, absent in the three converters. In agreement with prior findings, alpha ERD and MMN may hold particular promise for predicting transition to psychosis among CHR patients.

A neurophysiological deficit in early visual processing in schizophrenia patients with auditory hallucinations.

Existing 67-channel event-related potentials, obtained during recognition and working memory paradigms with words or faces, were used to examine early visual processing in schizophrenia patients prone to auditory hallucinations (AH, n = 26) or not (NH, n = 49) and healthy controls (HC, n = 46). Current source density (CSD) transforms revealed distinct, strongly left- (words) or right-lateralized (faces; N170) inferior-temporal N1 sinks (150 ms) in each group. N1 was quantified by temporal PCA of peak-adjusted CSDs. For words and faces in both paradigms, N1 was substantially reduced in AH compared with NH and HC, who did not differ from each other. The difference in N1 between AH and NH was not due to overall symptom severity or performance accuracy, with both groups showing comparable memory deficits. Our findings extend prior reports of reduced auditory N1 in AH, suggesting a broader early perceptual integration deficit that is not limited to the auditory modality.

Demonstrating test-retest reliability of electrophysiological measures for healthy adults in a multisite study of biomarkers of antidepressant treatment response

Growing evidence suggests that loudness dependency of auditory evoked potentials (LDAEP) and resting EEG alpha and theta may be biological markers for predicting response to antidepressants. In spite of this promise, little is known about the joint reliability of these markers, and thus their clinical applicability. New standardized procedures were developed to improve the compatibility of data acquired with different EEG platforms, and used to examine test-retest reliability for the three electrophysiological measures selected for a multisite project-Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care (EMBARC). Thirty-nine healthy controls across four clinical research sites were tested in two sessions separated by about 1 week. Resting EEG (eyes-open and eyes-closed conditions) was recorded and LDAEP measured using binaural tones (1000 Hz, 40 ms) at five intensities (60-100 dB SPL). Principal components analysis of current source density waveforms reduced volume conduction and provided reference-free measures of resting EEG alpha and N1 dipole activity to tones from auditory cortex. Low-resolution electromagnetic tomography (LORETA) extracted resting theta current density measures corresponding to rostral anterior cingulate (rACC), which has been implicated in treatment response. There were no significant differences in posterior alpha, N1 dipole, or rACC theta across sessions. Test-retest reliability was .84 for alpha, .87 for N1 dipole, and .70 for theta rACC current density. The demonstration of good-to-excellent reliability for these measures provides a template for future EEG/ERP studies from multiple testing sites, and an important step for evaluating them as biomarkers for predicting treatment response.

Heterogeneity of Auditory Verbal Working Memory in Schizophrenia

The heterogeneity of schizophrenia remains an obstacle for understanding its pathophysiology. Studies using a tone discrimination screening test to classify patients have found evidence for 2 subgroups having either a specific deficit in verbal working memory (WM) or deficits in both verbal and nonverbal memory. This study aimed to (a) replicate in larger samples differences between these subgroups in auditory verbal WM; (b) evaluate their performance on tests of explicit memory and sustained attention; (c) determine the relation of verbal WM deficits to auditory hallucinations and other symptoms; and (d) examine medication effects. The verbal WM and tone discrimination performance did not differ between medicated (n = 45) and unmedicated (n = 38) patients. Patients with schizophrenia who passed the tone screening test (discriminators; n = 60) were compared with those who did not (nondiscriminators; n = 23) and healthy controls (n = 47). The discriminator subgroup showed poorer verbal WM than did controls and a deficit in verbal but not visual memory on the Wechsler Memory Scale-Revised (Wechsler, 1987), whereas the nondiscriminator subgroup showed overall poorer performance on both verbal and nonverbal tests and a marked deficit in sustained attention. Verbal WM deficits in discriminators were correlated with auditory hallucinations but not with negative symptoms. The results are consistent with a verbal memory deficit in a subgroup of schizophrenia having intact auditory perception, which may stem from dysfunction of language-related cortical regions, and a more generalized cognitive deficit in a subgroup having auditory perceptual and attentional dysfunction.

Neuronal generator patterns at scalp elicited by lateralized aversive pictures reveal consecutive stages of motivated attention.

Event-related potential (ERP) studies have provided evidence for an allocation of attentional resources to enhance perceptual processing of motivationally salient stimuli. Emotional modulation affects several consecutive components associated with stages of affective-cognitive processing, beginning as early as 100-200ms after stimulus onset. In agreement with the notion that the right parietotemporal region is critically involved during the perception of arousing affective stimuli, some ERP studies have reported asymmetric emotional ERP effects. However, it is difficult to separate emotional from non-emotional effects because differences in stimulus content unrelated to affective salience or task demands may also be associated with lateralized function or promote cognitive processing. Other concerns pertain to the operational definition and statistical independence of ERP component measures, their dependence on an EEG reference, and spatial smearing due to volume conduction, all of which impede the identification of distinct scalp activation patterns associated with affective processing. Building on prior research using a visual half-field paradigm with highly controlled emotional stimuli (pictures of cosmetic surgery patients showing disordered [negative] or healed [neutral] facial areas before or after treatment), 72-channel ERPs recorded from 152 individuals (ages 13-68years; 81 female) were transformed into reference-free current source density (CSD) waveforms and submitted to temporal principal components analysis (PCA) to identify their underlying neuronal generator patterns. Using both nonparametric randomization tests and repeated measures ANOVA, robust effects of emotional content were found over parietooccipital regions for CSD factors corresponding to N2 sink (212ms peak latency), P3 source (385ms) and a late centroparietal source (630ms), all indicative of greater positivity for negative than neutral stimuli. For the N2 sink, emotional effects were right-lateralized and modulated by hemifield, with larger amplitude and asymmetry for left hemifield (right hemisphere) presentations. For all three factors, more positive amplitudes at parietooccipital sites were associated with increased ratings of negative valence and greater arousal. Distributed inverse solutions of the CSD-PCA-based emotional effects implicated a sequence of maximal activations in right occipitotemporal cortex, bilateral posterior cingulate cortex, and bilateral inferior temporal cortex. These findings are consistent with hierarchical activations of the ventral visual pathway reflecting subsequent processing stages in response to motivationally salient stimuli.

Motivated attention and family risk for depression: Neuronal generator patterns at scalp elicited by lateralized aversive pictures reveal blunted emotional responsivity

Behavioral and electrophysiologic evidence suggests that major depression (MDD) involves right parietotemporal dysfunction, a region activated by arousing affective stimuli. Building on prior event-related potential (ERP) findings (Kayser et al. 2016 NeuroImage 142:337–350), this study examined whether these abnormalities also characterize individuals at clinical high risk for MDD. We systematically explored the impact of family risk status and personal history of depression and anxiety on three distinct stages of emotional processing comprising the late positive potential (LPP). ERPs (72 channels) were recorded from 74 high and 53 low risk individuals (age 13–59 years, 58 male) during a visual half-field paradigm using highly-controlled pictures of cosmetic surgery patients showing disordered (negative) or healed (neutral) facial areas before or after treatment. Reference-free current source density (CSD) transformations of ERP waveforms were quantified by temporal principal components analysis (tPCA). Component scores of prominent CSD-tPCA factors sensitive to emotional content were analyzed via permutation tests and repeated measures ANOVA for mixed factorial designs with unstructured covariance matrix, including gender, age and clinical covariates. Factor-based distributed inverse solutions provided descriptive estimates of emotional brain activations at group level corresponding to hierarchical activations along ventral visual processing stream. Risk status affected emotional responsivity (increased positivity to negative-than-neutral stimuli) overlapping early N2 sink (peak latency 212 ms), P3 source (385 ms), and a late centroparietal source (630 ms). High risk individuals had reduced right-greater-than-left emotional lateralization involving occipitotemporal cortex (N2 sink) and bilaterally reduced emotional effects involving posterior cingulate (P3 source) and inferior temporal cortex (630 ms) when compared to those at low risk. While the early emotional effects were enhanced for left hemifield (right hemisphere) presentations, hemifield modulations did not differ between risk groups, suggesting top-down rather than bottom-up effects of risk. Groups did not differ in their stimulus valence or arousal ratings. Similar effects were seen for individuals with a lifetime history of depression or anxiety disorder in comparison to those without. However, there was no evidence that risk status and history of MDD or anxiety disorder interacted in their impact on emotional responsivity, suggesting largely independent attenuation of attentional resource allocation to enhance perceptual processing of motivationally salient stimuli. These findings further suggest that a deficit in motivated attention preceding conscious awareness may be a marker of risk for depression.

Lateralization for speech predicts therapeutic response to cognitive behavioral therapy for depression.

A prior study (Bruder, G.E., Stewart, J.W., Mercier, M.A., Agosti, V., Leite, P., Donovan, S., Quitkin, F.M., 1997. Outcome of cognitive-behavioral therapy for depression: relation of hemispheric dominance for verbal processing. Journal of Abnormal Psychology 106, 138-144.) found left hemisphere advantage for verbal dichotic listening was predictive of clinical response to cognitive behavioral therapy (CBT) for depression. This study aimed to confirm this finding and to examine the value of neuropsychological tests, which have shown promise for predicting antidepressant response. Twenty depressed patients who subsequently completed 14 weeks of CBT and 74 healthy adults were tested on a Dichotic Fused Words Test (DFWT). Patients were also tested on the National Adult Reading Test to estimate IQ, and word fluency, choice RT, and Stroop neuropsychological tests. Left hemisphere advantage on the DFWT was more than twice as large in CBT responders as in non-responders, and was associated with improvement in depression following treatment. There was no difference between responders and non-responders on neuropsychological tests. The results support the hypothesis that the ability of individuals with strong left hemisphere dominance to recruit frontal and temporal cortical regions involved in verbal dichotic listening predicts CBT response. The large effect size, sensitivity and specificity of DFWT predictions suggest the potential value of this brief and inexpensive test as an indicator of whether a patient will benefit from CBT for depression.