The effect of psychotropic drugs on cortical excitability and plasticity measured with transcranial magnetic stimulation: Implications for psychiatric treatment.

OBJECTIVE: Repetitive transcranial magnetic stimulation (rTMS) is an emerging treatment for neuropsychiatric disorders. Patients in rTMS treatment typically receive concomitant psychotropic medications, which affect neuronal excitability and plasticity and may interact to affect rTMS treatment outcomes. A greater understanding of these drug effects may have considerable implications for optimizing multi-modal treatment of psychiatric patients, and elucidating the mechanism(s) of action (MOA) of rTMS. METHOD: We summarized the empirical literature that tests how psychotropic drugs affect cortical excitability and plasticity, using varied experimental TMS paradigms. RESULTS: Glutamate antagonists robustly attenuate plasticity, largely without changes in excitability per se; antiepileptic drugs show the opposite pattern of effects, while calcium channel blockers attenuate plasticity. Benzodiazepines have moderate and variable effects on plasticity, and negligible effects on excitability. Antidepressants with potent 5HT transporter inhibition reduce both excitability and alter plasticity, while antidepressants with other MOAs generally lack either effect. Catecholaminergic drugs, cholinergic agents and lithium have minimal effects on excitability but exhibit robust and complex, non-linear effects in TMS plasticity paradigms. LIMITATIONS: These effects remain largely untested in sustained treatment protocols, nor in clinical populations. In addition, how these medications impact clinical response to rTMS remains largely unknown. CONCLUSIONS: Psychotropic medications exert robust and varied effects on cortical excitability and plasticity. We encourage the field to more directly and fully investigate clinical pharmaco-TMS studies to improve outcomes.

Cognitive rehabilitation group intervention for breast cancer survivors: results of a randomized clinical trial.

PURPOSE: We conducted a randomized clinical trial evaluating the efficacy of a cognitive rehabilitation (CR) intervention compared with a wait list (WL) control condition on cognitive complaints, neuropsychological and brain functioning in breast cancer survivors (BCS). METHODS: The small group intervention of five sessions included psychoeducation and cognitive exercises. ELIGIBILITY: Disease-free BCS with cognitive complaints, diagnosed with stage I, II or III breast cancer, completed primary treatment 18 months to 5 years earlier. Neurocognitive test data and cognitive complaints on the Patient's Assessment of Own Functioning Inventory (PAOFI) were assessed at baseline (T1), immediately post-intervention (T2), and 2 months later (T3). A subgroup of participants underwent resting state quantitative electroencephalography (qEEG) at all three assessment time points. RESULTS: Forty-eight participants [mean age (SD) 53.8 (8.2)] completed T1 assessments, and 29 participants had analyzable qEEG data. The CR group improved significantly over time compared with the WL group on PAOFI total and memory scores (both p = .01) and on Rey Auditory Verbal Learning Test (RAVLT) total (trials I-V) (p = .02) and RAVLT delayed recall (p = .007) scores. On qEEG, the CR group showed a significant decrease in delta 'slow wave' power (p = .02) and an increase in the frontal distribution of alpha power (p = .04) from T1 to T2. CONCLUSIONS: BCS in the CR group showed immediate and sustained improvements in self-reported cognitive complaints and memory functioning on neurocognitive testing. Results of the qEEG substudy provide some support for neurophysiological changes underlying the intervention. Copyright © 2015 John Wiley & Sons, Ltd.

Evaluation of quantitative EEG by classification and regression trees to characterize responders to antidepressant and placebo treatment.

The study objective was to evaluate the usefulness of Classification and Regression Trees (CART), to classify clinical responders to antidepressant and placebo treatment, utilizing symptom severity and quantitative EEG (QEEG) data. Patients included 51 adults with unipolar depression who completed treatment trials using either fluoxetine, venlafaxine or placebo. Hamilton Depression Rating Scale (HAM-D) and single electrodes data were recorded at baseline, 2, 7, 14, 28 and 56 days. Patients were classified as medication and placebo responders or non-responders. CART analysis of HAM-D scores showed that patients with HAM-D scores lower than 13 by day 7 were more likely to be treatment responders to fluoxetine or venlafaxine compared to non-responders (p=0.001). Youden's index γ revealed that CART models using QEEG measures were more accurate than HAM-D-based models. For patients given fluoxetine, patients with a decrease at day 2 in θ cordance at AF2 were classified by CART as treatment responders (p=0.02). For those receiving venlafaxine, CART identified a decrease in δ absolute power at day 7 at the PO2 region as characterizing treatment responders (p=0.01). Using all patients receiving medication, CART identified a decrease in δ absolute power at day 2 in the FP1 region as characteristic of nonresponse to medication (p=0.003). Optimal trees from the QEEG CART analysis primarily utilized cordance values, but also incorporated some δ absolute power values. The results of our study suggest that CART may be a useful method for identifying potential outcome predictors in the treatment of major depression.

Brain functional changes (QEEG cordance) and worsening suicidal ideation and mood symptoms during antidepressant treatment.

OBJECTIVE: Antidepressant medications are efficacious overall; however, some individuals experience worsening mood symptoms and increased suicidal ideation (SI) during treatment. We examined the quantitative electroencephalographic (QEEG) cordance biomarker of brain function biomarker in relation to treatment-emergent symptom worsening. METHOD: Seventy-two major depressive disorder (MDD) subjects were treated with fluoxetine 20 mg (n = 13), venlafaxine 150 mg (n = 24), or placebo (n = 35) under double-blind conditions. Behavioral ratings determined whether each subject demonstrated worsening of depressed mood, anxiety, or SI during treatment. QEEG cordance data were analyzed to determine whether symptom worsening was associated with neurophysiological changes. RESULTS: Antidepressant treatment-emergent SI (13.5%) was associated with a large transient decrease in midline-and-right-frontal (MRF) cordance 48 h after start of medication. CONCLUSION: Hypothesis-generating results suggest a pattern of functional changes in midline and right frontal brain regions associated with antidepressant treatment-emergent SI in MDD.

Painful physical symptoms and treatment outcome in major depressive disorder: a STAR*D (Sequenced Treatment Alternatives to Relieve Depression) report.

BACKGROUND: Painful physical symptoms (PPS) are both common and reduce the likelihood of remission in major depressive disorder (MDD), based upon results of clinical trials in selected populations. Whether PPS significantly contribute to poorer treatment outcome overall in primary or specialty psychiatric care settings remains unclear. METHOD: Out-patients (n=2876) with MDD were treated in the first step of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial with citalopram up to 60 mg/day for up to 14 weeks. Presence of painful symptoms, as well as severity of depression, physical illness, and demographic and treatment factors were examined. Time to and overall rates of remission were analysed in relation to the presence of PPS. RESULTS: Of the participants, 80% complained of PPS. These patients, both in primary and specialty psychiatric settings, had significantly lower remission rates and took longer to remit. Increasing severity of PPS was associated with greater physical illness burden, lower socio-economic status, absence of private insurance and being female, African-American or Hispanic. After adjustment for these factors, patients with PPS no longer had significantly poorer treatment outcomes. CONCLUSIONS: Presence and severity of PPS is an indicator of MDD that may have poorer treatment outcome with an initial selective serotonin reuptake inhibitor. These poorer treatment outcomes are multifactorial, however, and are not explained by the presence and severity of pain per se.

Brain functional changes during placebo lead-in and changes in specific symptoms during pharmacotherapy for major depression.

OBJECTIVE: Brain functional changes during placebo lead-in have been associated with antidepressant response in clinical trials for major depressive disorder (MDD); however, the relationship between such non-pharmacodynamic changes in brain function and changes in specific symptoms is unknown. METHOD: Fifty-eight adults with MDD completed a 1-week single-blind placebo lead-in preceding 8 weeks of double-blind randomized treatment with fluoxetine or venlafaxine (n = 30) or placebo (n = 28). Brain functional change during lead-in was assessed using quantitative electroencephalographic (qEEG) prefrontal theta-band cordance. Symptoms were assessed using the Symptom Checklist-90-Revised (SCL-90-R). RESULTS: The multiple regression model examining the qEEG parameter in relation to SCL-90-R subscales was significant [F(9,9) = 4.27, P = 0.021, R(2) = 0.81] in females, with a significant association for the interpersonal sensitivity subscale (beta coefficient = 1.94, P = 0.001). CONCLUSION: Prefrontal neurophysiologic change during placebo lead-in may indicate subsequent antidepressant-related improvement in symptoms of interpersonal sensitivity.

Prefrontal changes and treatment response prediction in depression.

A continuing challenge in the treatment of depression is how to determine whether an effective drug has been selected for a particular patient, given that individuals will respond to some antidepressants but not others. The factors that contribute to response for each person have been examined from a variety of perspectives, both psychological and physiological. Advances in neuroimaging and in quantitative electroencephalography (QEEG) have made it possible to examine features of brain activity that are associated with response. A new QEEG measure, cordance, is correlated with regional cortical perfusion, and has been used with retrospective and prospective studies to evaluate specific findings that are predictive of clinical response in major depression. We present here a series of depressed subjects treated with antidepressants of different classes; decreases in prefrontal activity were seen as early as 48 hours into treatment in responders and were absent in nonresponders. These findings suggest a role for the prefrontal region in mediating response to medications with different mechanisms of action and raise the possibility of using new QEEG measures to identify changes in brain activity that are predictive of clinical outcome from antidepressant treatment.

Executive dysfunction predicts nonresponse to fluoxetine in major depression.

BACKGROUND: Functional brain imaging studies of major depression have consistently revealed hypometabolism or hypoperfusion in specific regions of the prefrontal cortex and basal ganglia. Studies of cognitive functioning in major depression have suggested that some but not all subjects exhibit cognitive deficits that are consistent with frontal-subcortical dysfunction, although the reasons for this heterogeneity are unclear. In this study, we explored this heterogeneity among depressed subjects by examining the relationship between cognitive functioning and treatment outcome. METHOD: Subjects with major depression were administered a complete neuropsychological test battery prior to treatment with fluoxetine. RESULTS: There were no significant differences between responders and nonresponders to fluoxetine in terms of age, educational achievement, number of past episodes of depression, and estimated premorbid IQ. However, nonresponders performed significantly worse than responders on several pretreatment measures of executive functioning, after controlling for baseline group differences in depression severity. LIMITATIONS: The results are based on a small sample of primarily female subjects, resulting in low statistical power and less generalizability to samples of male subjects with depression. CONCLUSIONS: The findings suggest that subtle prefrontal dysfunction in subjects with major depression may be predictive of poor response with particular medications. Assessment of the executive functions may play a particular role in pretreatment identification of subjects likely to respond to specific medications.

Attenuation of brain high frequency electrocortical response after thiopental in early stages of Alzheimer's dementia.

RATIONALE: Pathological brain regions generate proportionately less high-frequency (beta) activity than non-pathological regions, a phenomenon accentuated by barbiturate administration. OBJECTIVES: Previously, we reported a loss of high-frequency brain electrical response to thiopental in dementia of the Alzheimer's type (DAT). The current study examines whether this phenomenon may be detected in early stages of the illness. METHODS: Using quantitative electroencephalography, we examined power in the 20-28 Hz band in patients with early DAT (n=7, age 71.0+/-3.2 years, Folstein Mini Mental State Score, MMSE 26.2+/-0.8), normal controls (n=8, age 74.3+/-3.2 years, MMSE 29.0+/-0.3) and subjects with moderately severe DAT (n=6, age 76.6+/-3.0 years, MMSE=12.5+/-3.7) at baseline and following an intravenous bolus of thiopental (0.5 mg/kg). RESULTS: No significant group differences in beta power were detectable at baseline. In response to thiopental, early DAT subjects compared to controls showed a significantly smaller beta power response in the frontal region at 1-3 min postinjection. Losses were smaller than those of subjects with moderately severe DAT and demonstrated a non-linear correlation with decreases in cognitive function as assessed by the MMSE score (r2=0.75). CONCLUSION: In early stages of DAT, a barbiturate challenge may unmask abnormalities in brain electrical activity not seen at baseline. Such changes may reflect underlying cortical deafferentation.

Clinical neurophysiology using electroencephalography in geriatric psychiatry: neurobiologic implications and clinical utility.

Electroencephalography (EEG) offers a unique contribution to the armamentarium of imaging technologies used in the evaluation of brain function. The primary clinical application of EEG is in the diagnosis of delirium, dementia, and epilepsy, which are frequently encountered in the practice of geropsychiatry. This review summarizes the principles behind generation of the EEG signal, its strengths and limitations as a technology, clinical indications for performing an EEG, the principles underlying quantitative EEG (QEEG), and how QEEG is allowing us to probe brain function and connectivity in new ways.

Relationship between brain electrical activity and cortical perfusion in normal subjects.

Cerebral glucose uptake and perfusion are accepted as tightly coupled measures of energy utilization in both normal and diseased brain. The coupling of brain electrical activity to perfusion has been demonstrated, however, only in the presence of chronic brain disease. Very few studies have examined the relationship between cerebral electrical activity and energy utilization in normal brain tissue. To clarify this relationship, we performed 33 H2(15)O-positron emission tomography (PET) scans in six normal subjects both at rest and during a simple motor task, and acquired surface-recorded quantitative electroencephalogram (QEEG) data simultaneously with isotope injection. We examined the associations between cerebral perfusion directly underlying each recording electrode and three QEEG measures (absolute power, relative power, and cordance). All EEG measures had moderately strong coupling with perfusion at most frequency bands, although the directions of the associations differed from those previously reported in subjects with stroke or dementia. Of the three QEEG measures examined, cordance had the strongest relationship with perfusion (multiple R2 = 0.58). Cordance and PET were equally effective in detecting lateralized activation associated with the motor task, while EEG power did not detect this activation. Electrodes in the concordant state had a significantly higher mean perfusion than those in the discordant state. These results indicate that normal brain electrical activity has a moderately strong association with cerebral perfusion. Cordance may be the most useful QEEG measure for monitoring cerebral perfusion in subjects without chronic brain disease.

Changes in electrocortical power and coherence in response to the selective cholinergic immunotoxin 192 IgG-saporin.

Changes in brain electrical activity in response to cholinergic agonists, antagonists, or excitotoxic lesions of the basal forebrain may not be reflective entirely of changes in cholinergic tone, in so far as these interventions also involve noncholinergic neurons. We examined electrocortical activity in rats following bilateral intracerebroventricular administration of 192 IgG-saporin (1.8 microg/ventricle), a selective cholinergic immunotoxin directed to the low-affinity nerve growth factor receptor p75. The immunotoxin resulted in extensive loss of choline acetyl transferase (ChAT) activity in neocortex (80%-84%) and hippocampus (93%), with relative sparing of entorhinal-piriform cortex (42%) and amygdala (28%). Electrocortical activity demonstrated modest increases in 1- to 4-Hz power, decreases in 20- to 44-Hz power, and decreases in 4- to 8-Hz intra- and interhemispheric coherence. Rhythmic slow activity (RSA) occurred robustly in toxin-treated animals during voluntary movement and in response to physostigmine, with no significant differences seen in power and peak frequency in comparison with controls. Physostigmine significantly increased intrahemispheric coherence in lesioned and intact animals, with minor increases seen in interhemispheric coherence. Our study suggests that: (1) electrocortical changes in response to selective cholinergic deafferentation are more modest than those previously reported following excitotoxic lesions; (2) changes in cholinergic tone affect primarily brain electrical transmission within, in contrast to between hemispheres; and (3) a substantial cholinergic reserve remains following administration of 192 IgG-saporin, despite dramatic losses of ChAT in cortex and hippocampus. Persistence of a cholinergically modulated RSA suggests that such activity may be mediated through cholinergic neurons which, because they lack the p75 receptor, remain unaffected by the immunotoxin.

Neurophysiologic predictors of treatment response to fluoxetine in major depression.

Treatment with antidepressants is marked by heterogeneity of response; predicting individual response to any given agent remains problematic. Neuroimaging studies suggest that response is accompanied by physiologic changes in cerebral energy utilization, but have not provided useful markers at pretreatment baseline. Using quantitative EEG (QEEG) techniques, we investigated pretreatment neurophysiologic features to identify responders and non-responders to fluoxetine. In a double-masked study, 24 adult subjects with current major depression of the unipolar type were studied over 8 weeks while receiving fluoxetine (20 mg QD) or placebo. Neurophysiology was assessed with QEEG cordance, a measure reflecting cerebral energy utilization. Response was determined with rating scales and clinical interview. Subjects were divided into discordant and concordant groups based upon the number of electrodes exhibiting discordance. The concordant group had a more robust response than the discordant group, judged by lower final Hamilton Depression (HAM-D) mean score (8.0+/-7.5 vs. 19.6+/-4.7, P = 0.01) and final Beck Depression Inventory (BDI) mean score (14.0+/-9.4 vs. 27.8+/-3.7, P = 0.015), and by faster reduction in symptoms (HAM-D: 14.0+/-5.0 vs. 23.8+/-4.1, P = 0.004 at 1 week). Groups did not differ on pretreatment clinical or historical features. Response to placebo was not predicted by this physiologic measure. We conclude that cordance distinguishes depressed adults who will respond to treatment with fluoxetine from those who will not. This measure detects a propensity to respond to fluoxetine and may indicate a more general responsiveness to antidepressants.

Altered cerebral energy utilization in late life depression.

BACKGROUND: Global and regional changes in cerebral energy utilization are reported to characterize late life depression. METHODS: Twenty seven subjects with late life depression (9 prior to starting medication, 18 after starting) and 27 matched controls were evaluated with cordance, a quantitative EEG measure that reflects cerebral energy utilization. RESULTS: Global and focal (anterior and centrotemporal) differences were present in theta-band cordance between unmedicated depressed and control subjects. Depressed subjects receiving treatment had cordance patterns similar to controls. CONCLUSIONS: The presence of both diffuse and focal disturbances in energy utilization prior to initiating treatment indicates that cordance detects altered cerebral physiology in depressed patients, and that this measure may also be sensitive to treatment interventions.

Effects of cholinergic deafferentation and NGF on brain electrical coherence.

Rats received unilateral lesions of the nucleus basalis and were infused intracerebroventricularly (i.c.v.) over 3 weeks with nerve growth factor (NGF) or vehicle. Electrocortical coherence was assessed at postoperative days 4, 7, 14, and 21 from all possible pairs of eight epidural electrodes in the delta (1-4 Hz), theta (4-8 Hz), alpha (8-12 Hz), beta-1 (12-20 Hz), and beta-2 (20-28 Hz) bands. On day 21 choline acetyltransferase (ChAT) activity was measured in cortical tissue underlying each electrode site. Lesions resulted in losses of interhemispheric, as well as bilateral intrahemispheric coherence in the theta band (F1,21 = 28.61, p < 0.0001, F1,21 = 4.30, p < 0.05), with no significant differences seen in other bands. Changes were accentuated during immobility compared with walking and exploratory behavior. Intrahemispheric changes were greatest within the lesioned hemisphere (F1,21 = 6.97, p < 0.01) in long connections between electrode pairings connecting frontal to posterior brain regions. Nerve growth factor (NGF) attenuated losses in ChAT (F1,21 = 21.31, p < 0.0001) and intrahemispheric coherence (F1,21 = 9.66, p < 0.005), whereas interhemispheric coherence showed no significant response. Intact animals receiving NGF showed increases in intrahemispheric coherence, as well as modest increases in ChAT. Increases in coherence in response to NGF occurred within 4-7 days following brain lesions, with no significant change during the 2 weeks thereafter. Our results suggest that coherence is sensitive to cholinergic deafferentation, particularly of long corticocortical connections. NGF differentially restores coherence within hemispheres, as opposed to between hemispheres. Our study suggests that brain function in Alzheimer's disease related to damage of transcallosal fiber tracts may not be responsive to cholinergic treatments. Future studies may wish to evaluate the cognitive relevance of NGF's effects on intact brain.

Assessing the accuracy of topographic EEG mapping for determining local brain function.

OBJECTIVE: There has been considerable discussion regarding the accuracy of topographic electroencephalographic (EEG) maps for assessing local cerebral function. We performed this study to test the accuracy of EEG mapping by examining the association between electrical activity and the perfusion under each electrode as another measure of local cerebral function. METHODS: EEG mapping was performed simultaneously with (H15)2O positron emission tomography (PET) scanning in 6 normal adult subjects, both at rest and during a simple motor task. EEG data were processed using 3 different montages; two EEG power measures (absolute and relative power) were examined. RESULTS: Relative power had much stronger associations with perfusion than did absolute power. In addition, calculating power for bipolar electrode pairs and averaging power over electrode pairs sharing a common electrode yielded stronger associations with perfusion than data from referential or single source montages. CONCLUSIONS: These findings indicate (1) that topographic EEG mapping can accurately reflect local brain function in a way that is comparable to other methods, and (2) that the choice of EEG measure and montage have a significant influence on the degree with which maps reflect this local activity and function.

Changes in cortical EEG and cholinergic function in response to NGF in rats with nucleus basalis lesions.

We examined whether recovery of cholinergic function in response to nerve growth factor (NGF) results in restoration of electrocortical activity. Rats received unilateral lesions of the nucleus basalis and were infused intracerebroventricularly (i.c.v.) over 3 weeks with NGF or vehicle. Cortical electrical activity was assessed at postoperative days 4, 7, 14, and 21 from 8 epidural electrodes. On day 21, choline acetyl transferase (ChAT) activity was measured in cortical tissue underlying each electrode site. Lesions resulted in increases in slow-wave (delta) power and decreases in high-frequency (beta 2) power in the lesioned, as well as the non-lesioned hemisphere. Changes correlated topographically and in magnitude with losses of ChAT activity and suggested that regional electrocortical function was affected by cholinergic activity originating in the ipsilateral, as well as the contralateral hemisphere. NGF attenuated changes in cholinergic and electrocortical function bilaterally, though in the lesioned hemisphere, function did not return to control levels. Likewise, intact animals receiving NGF showed increases in beta 2-power, as well as modest increases in ChAT activity. Changes in brain electrical activity in response to NGF occurred within 4-7 days without significant changes during the 2 weeks thereafter. Our results suggest that outcomes of future animal and human trials-using unilateral i.c.v. infusions of NGF need to consider the reciprocal influences of hemispheric cholinergic function, as well as possible effects of NGF on intact brain.

Loss of high-frequency brain electrical response to thiopental administration in Alzheimer's-type dementia.

Abnormal brain regions generate proportionately less high-frequency (beta) activity than nonpathological regions, a phenomenon accentuated by barbiturate administration. Using quantitative electroencephalography we examined power in the 20- to 28-Hz band in patients with dementia of the Alzheimer's type (DAT), vascular dementia (VaD), and normal elderly controls (CON) following an IV bolus of thiopental (0.5 mg/kg). Compared to both CON and VaD subjects, DAT subjects showed a marked loss of beta power elicited across the cortex, with largest differences noted in the frontal region. Losses were most significant for the peak response recorded at 30 to 90 s postinjection and persisted during the 5-minute follow-up period. We hypothesize that differences in this electrocerebral response reflect differences in the underlying neuropathology of DAT and VaD subjects. A thiopental challenge may be well suited for the in vivo assessment of brain function in dementias characterized by prominent cortical pathology.

Brain structure and function and the outcomes of treatment for depression.

BACKGROUND: Depressed patients have a variety of brain structural alterations, the most common being atrophy and deep white-matter lesions. Alterations in brain function also are common, particularly regional decreases in cerebral metabolism and perfusion. METHOD: We review here the evidence that alterations in brain structure and function may explain some of the heterogeneity in outcomes of depression. We also report initial results suggesting that measurement of brain structure and function may help to predict outcomes of treatment for depression. Brain structure was examined using three-dimensional reconstruction and volumetric analysis of magnetic resonance imaging (MRI) scans. Brain function was examined using quantitative electroencephalography (QEEG), performed at baseline and serially during the course of treatment. QEEG measures included coherence (a measure of synchronized activity between brain regions) and cordance (a measure strongly associated with regional cerebral perfusion). RESULTS: Depressed patients have been reported to have larger volumes of white-matter lesions than controls. We have found that some types of white-matter lesions are associated with lower coherence and that subjects with low coherence had significantly poorer outcomes of treatment for depression at 2-year follow-up. Depressed subjects had low cordance at baseline, which decreased further during the course of effective treatment. Subjects who did not improve had little or no change in cordance. Changes in cordance were detected prior to the onset of clinical response, with decreases seen as early as 48 hours after the initiation of treatment in subjects who showed eventual response. CONCLUSION: These preliminary results suggest that functional imaging using QEEG may be useful for assessing, and possibly predicting, outcomes of treatment for depression.