Electrophysiological and behavioral correlates of psychomotor responsivity in depression.

Psychomotor retardation is a frequently observed clinical feature of depressive states. This study attempted to assess the relationship between response slowness and central nervous system (CNS) activity by examining cortical evoked potentials (EPs) during psychomotor task performance. Patients consisted of 21 women who met Research Diagnostic Criteria (RDC) and exhibited a minimum Hamilton Rating Scale for Depression score of 18 at the end of a drug washout period, the scheduled time of testing. The same number of normal women with no history of psychiatric illness were employed as controls. Cortical EPs from Cz and integrated electromyogram (EMG) from the dominant forearm extensor were recorded and time-locked to warning and imperative stimuli of a standard, two-choice, fixed foreperiod reaction time (RT) task, which yielded behavioral measures of decision time (DT) and movement time (MT). Analysis focused on behavioral RTs, latency and amplitudes of EMG, sensory and slow cortical (CNV) EPs, and measures of input time (IPT), central processing time (CPT), and motor execution time (MET), derived from combinations of EP and EMG peak latencies. Patients exhibited slower DT and MT response times, delayed EMG latencies, and attenuated EP amplitudes. The derived CPT measure was also significantly longer in patients. These findings support the view that a central dysfunction is implicated in psychomotor retardation, and the results are discussed in relation to information processing theory.

The effect of acute tryptophan depletion and fenfluramine on quantitative EEG and mood in healthy male subjects.

BACKGROUND: Efforts to model putative serotonergic deficits associated with affective disorders have frequently involved acute tryptophan depletion (ATD) as a manipulation strategy aimed at lowering brain serotonin synthesis. In an attempt to widen the scope of the measurement probes used in these investigations, the central actions of ATD and a subsequent dose of fenfluramine were examined via utilization of quantitative electroencephalography (EEG) and mood ratings. METHODS: Electroencephalograms (EEG) and subjective mood ratings were assessed in 28 healthy men before and after double-blind ingestion of a tryptophan-depleting (T-) amino acid mixture, or a nutritionally balanced (B) amino acid mixture containing tryptophan, and again after a single-blind oral dose of D,L-fenfluramine hydrochloride (60 mg). RESULTS: Compared to the B mixture, the T- mixture reduced total plasma tryptophan by more than 75% 5 hours after ingestion. Tryptophan depletion was associated with a modest lowering of mood and a slowing of EEG as indicated by increases in delta amplitude. Fenfluramine caused no change in mood but increased fast wave (beta) activity in anterior recordings when administered after the T-, but not after the B mixture. CONCLUSIONS: Quantitative EEG measurements may be a promising method for studying the central mechanisms underlying serotonin-mediated changes in mood and behavior.

Influence of acute tryptophan depletion on mood and immune measures in healthy males.

Depressive illness has been associated with variations of several aspects of immune functioning, as well as alterations of cytokine production in stimulated lymphocytes. In the present investigation we sought to determine whether pharmacologically-induced reductions of mood in healthy, male subjects would be associated with alterations in the levels of circulating IL-1 beta or IL-6 or to in vitro lymphocyte proliferation in response to T cell mitogens, PHA and Con A. Lowering tryptophan levels by means of a tryptophan-deficient amino acid mixture, which reduced plasma tryptophan and serotonin (5-HT) levels, produced a lowering of mood in a subset of male subjects (that had no personal or family history of depression) relative to subjects that received a balanced amino acid mixture. Correlational analyses revealed that the change of mood (particularly depression and anger) in subjects that received the tryptophan-free mixture was related to the extent of the tryptophan or 5-HT reductions. However, while fenfluramine administration resulted in recovery of tryptophan and 5-HT levels, this was not accompanied by recovery of mood. Furthermore, it was observed that the lowering of tryptophan levels and the reduced mood were not accompanied by variations of the cytokine levels or cell proliferation. Evidently, transient and modest alterations of 5-HT or mood induced by a tryptophan-free amino acid mixture were insufficient to promote variations of immune activity or circulating IL-1 beta or IL-6 levels. Even if depression were related to immune disturbances, the mood and 5-HT alterations associated with this type of manipulation may be too brief to promote immune changes comparable with those ordinarily associated with severe or chronic depressive illness.

Separate and combined effects of alcohol and tobacco on the amplitude of the contingent negative variation.

To examine the separate and combined effects of alcohol and tobacco smoking on cortical functioning, the amplitude of the contingent negative variation (CNV) was studied during a simple reaction time task in non-smokers, tobacco-deprived smokers and non-deprived smokers in sessions involving administration of four cigarettes and/or 0.65 g/kg ethyl alcohol. Computer analysis indicated that alcohol and combined alcohol + tobacco significantly reduced the CNV amplitude in non-deprived smokers. Two sub-groups of non-smokers were identified, one showing large pre-drug CNV amplitudes and significant alcohol-induced reductions and the other showing small pre-drug amplitudes and no change in CNV amplitude after alcohol. No significant results were observed with alcohol, tobacco or alcohol + tobacco combined in tobacco-deprived smokers. The results are discussed in relation to previously reported studies which have indicated both synergistic and antagonistic interactions between alcohol and tobacco, and suggestions are forwarded regarding the experimental and clinical significance of tobacco-induced enhancement of CNV amplitude reduction by alcohol.

Neuroelectrical activity related to panic disorder.

1. Quantitative electroencephalographic activity (EEG), together with bioelectric measures of the peripheral nervous system, provide us with unique non-invasive tools for investigating neurobiological issues relating to panic disorder. 2. During recordings of non-panic states, patients with panic disorder exhibit a desynchrony in autonomic vs. somatic arousal levels and also display significant EEG correlations with self-reported anxiety which are not apparent in control subjects. 3. Recordings concomitant with self-reported anxiety/panic during lactate infusions are associated with increased autonomic and somatic arousal and a paradoxical increase in slow wave EEG activity. 4. EEG recordings throughout a lactate challenge indicate that slow wave activity associated with panic does not appear to be characterized by an abrupt, sudden onset but tends to increase gradually throughout the infusion, a finding which is in disaccord with the 'spontaneity' view of panic.

Neuropsychophysiological correlates of lactate-induced panic.

1. One of the simplest and most direct applications of neuropsychophysiological techniques is to anxiety disorders. 2. The physiological changes accompanying the lactate induction of panic appear, for most response systems, to be similar to those found spontaneously in anxious patients and are characteristic of a state of hyperarousal. 3. Patients vulnerable to lactate-induced panic exhibit higher than normal pre-panic autonomic activity, elevated autonomic-somatic activity during lactate-induced panic and an EEG response to provoked panic which appears to be comprised of a "paradoxical" shift towards slow wave delta activity and an altered brainstem evoked response. 4. Additional studies are warranted to determine the relationship of these physiological changes to the triggering of panic and preliminary attempts in this direction are discussed.

Temporal segmentation of response speed in depression: neuro-electrophysiological approaches.

1. Depressive psychomotor retardation, as observed by delayed reaction times (RT), may be related to a slowing in information processing speed. 2. Two separate studies compared indices of information processing speed in depressed patients and non-clinical controls by segmenting behavioral RT with brain event-related potentials (ERPs) and electromyographic (EMG) responses. 3. In Study I, slower behavioral RTs in depression were concomitant with slower central processing times (CPT) but not motor execution times (MET). 4. In Study II, P165, a putative early cognitive ERP related to 'stimulus evaluation time', was found to be slower but within normal range in depressed patients.

Computerized EEG correlates of depression and antidepressant treatment.

Quantitative EEG was used to examine: differences between non-medicated depressives and normal controls; chronic effects of antidepressant drug treatment. Spectral analysis of cortical EEG activity revealed: significant group differences in slow and fast wave activity and significant differences in hemispheric asymmetry; limited effects of antidepressants which were restricted to slow wave activity. Group differences are supportive of cortical disactivation of the right-hemisphere in depressive disorders and the limited drug-EEG effects in depressives argue for additional studies on multi-lead oriented pharmaco-EEG profiles in psychiatric populations.

Cortical slow potential shifts in tardive dyskinesia.

1. Slow cortical potential shifts such as the late terminal E-wave component of the CNV appear to be determined mainly by the level of motor preparation and as such it was employed to investigate the degree of cortical involvement in schizophrenics exhibiting abnormal motor phenomena induced by prolonged treatment with neuroleptics. 2. The basic experimental task was a constant foreperiod warned reaction time task consisting of a brief warning tone (S1) followed 4 sec later by a light, the imperative stimulus (S2), upon which the subject was instructed to release a response key. The task was presented twice, in a randomized order, under neutral and fast set instructions, to tardive (TD) and non-tardive dyskinesia (NTD) groups. 3. Computer EEG analysis identified and analysed on early O-wave measured as the average amplitude 500-1000 msec post S1, and the latter E-wave measured as the average amplitude 500 msec prior to S2. Two additional epochs of PINV activity were also analysed. 4. The results indicated that the TD group exhibited significantly larger PINV activity, but unlike NTD patients, the TD group failed to exhibit any significant increases in E-wave amplitude concommitant with improved behavioral reaction times. The results are discussed in relation to a disinhibitory theory of tardive dyskinesia.

Preparatory brain potentials in major depressive disorder.

1. Psychomotor slowing in depression is frequently reflected by delayed reaction times (RT). 2. The role of central arousal mechanisms in response slowing was examined by comparing scalp-recorded slow negative potentials of depressed patients with normal controls in two separate studies. 3. Varying fore-warned RT conditions elicited contingent negative variation (CNV) waveforms and the resultant mid-point amplitudes of these waveforms together with orienting (O-wave), expectancy (E-wave) and post-imperative negative variation (PINV) component amplitudes and sensory evoked responses (N1, P2) were compared between groups. 4. RTs were significantly slowed in depressed patients and the patient group exhibited consistently larger PINV amplitudes. Depending on the RT condition, patients also exhibited larger mid-point CNV amplitudes and smaller N1 and P2 amplitudes.

Quantitative EEG in the prediction of antidepressant response to imipramine.

The purpose of this study was to examine the utility of quantitative electroencephalography (QEEG) in the prediction of response to imipramine in depressed patients. Forty patients with a diagnosis of unipolar depression were subjected to a placebo washout and were assessed at pre-drug, 3 h after their first dose of imipramine, and again 2 weeks into treatment. Following 4 weeks of open imipramine treatment, patients were separated into responder (R) and non-responder (NR) groups. Statistical analysis of the 29 patients who completed the study focused on group comparisons of power spectral estimates in four frequency bands from multi-channel recordings. Results showed that theta power differentiated R and NR groups prior to treatment, in response to an acute test dose, as well as after 2 weeks of active drug treatment. Results based on this exploratory study suggest that QEEG may be a useful early predictor of response to imipramine.

Quantitative EEG correlates of panic disorder.

Quantitative analysis of electroencephalographic (EEG) signals recorded from multiple scalp sites was used to compare panic disorder patients (n = 34) with normal healthy controls. Patients exhibited greater overall absolute power in the delta, theta, and alpha frequency bands and less relative power in the beta band. Discriminant analysis of absolute power indices correctly classified 75% of the subjects, while relative power indices exhibited a 69% correct-classification rate. Absolute delta and theta power were positively correlated with observer ratings of anxiety, while relative beta power was related to self-ratings of anxiety.

Effects of cigarette smoking on subjective and brain evoked responses to electrical pain stimulation.

The effects of smoking two cigarettes on brain evoked potentials (EP) and subjective ratings (SR) of pain intensity to 3 levels of electrical skin stimulation were investigated in 14 female habitual smokers. Smoking increased EP amplitudes to all stimulus intensities, but did not alter SRs. Changes in SRs to intensities in the pain range, but not in the prepain range, were found to be negatively correlated with smoke inhalation as measured by expired alveolar carbon monoxide (CO) elevations. No significant EP-smoking inhalation correlations were observed.

Subjective and brain-evoked responses to electrical pain stimulation: effects of cigarette smoking and warning condition.

Infrahuman studies employing behavioral indices of pain reactivity have supported a central antinociceptive action of nicotine which appears to be selective and dependent on the class of pain elicited. Human investigations employing subjectively based ratings and judgments of pain intensity have been less conclusive regarding the painfulness of stimuli following nicotine/smoking administration. As the more objective brain-evoked potential (EP) measure has been shown to reflect pain intensity and to be sensitive to a variety of analgesics, this study attempted to examine, together with subjective responses, the effects of cigarette smoking on EPs to pain stimuli administered under varying warning conditions. Twelve male and twelve female smokers served as experimental subjects. In smoking and nonsmoking sessions, subjective intensity ratings (SR) and vertex EPs were assessed in response to electrical skin stimuli presented at a level 20% above pain threshold. Stimulation was either nonwarned or warned with warning conditions involving single or repeated presentations of electrical current at constant or increasing intensities 12 seconds prior to pain stimulation. SRs and peak-to-peak N1-P2 EP amplitudes were measured for each smoking session and warning condition. A significant condition effect was observed for SRs with increasing prepain warning stimulation resulting in the greatest pain ratings. Although smoking did not directly alter SRs or EPs to pain, smoking exposure, as measured by carbon monoxide, was found to be differentially correlated with EP alterations in male and female smokers depending on the warning condition.

Aging, smoking and EEG coherence: a preliminary study.

Although the cigarette smoking habit is prevalent in young, middle aged and elderly adults, it is yet unknown whether a long term smoking history alters the aging brain and/or whether the aging brain demonstrates an altered sensitivity to acute smoking. Inter- and intrahemispheric EEG coherence was compared in 20 young (18-39 years) adults (10 smokers, 10 nonsmokers) and 20 elderly (64-81 years) adults (10 smokers, 10 nonsmokers). The acute effects of sham inhaling on a nonlighted cigarette and cigarette smoking on EEG coherence was also compared in young and elderly adult smokers. In general, elderly adults exhibited reduced interhemispheric coherence values relative to young adults and, depending on the frequency band, age effects varied with recording site. Smokers of both age groups exhibited greater interhemispheric total alpha coherence values than nonsmokers. Similar smoker status effects were found with fast alpha but this varied with recording site. Relative to sham smoking, acute cigarette smoking reduced interhemispheric slow alpha in both young and elderly smokers but reduced total alpha coherence only in elderly smokers. The results are discussed in relation to normal and pathological aging, including dementia.

Electroencephalographic characterization of cigarette smoking behavior.

The rewarding properties of used and abused substances are related to their ability to modulate central processes subserving mood, cognition, and behavior. Research into the motivationally relevant factors mediating substance use and abuse among human beings, including tobacco smoking, can strategically benefit from the utilization of noninvasive brain function measures that are able to probe the neurobiology of brain states in concert with substance ingestion. This paper reviews investigations from my laboratory with the use of neuroelectric tools, by means of quantitative electroencephalography, for the purpose of characterizing the central response to cigarette smoking. Prominent in these strategies is the acute smoking paradigm, whereby measures are focused on the profiling of central responsivity to smoke inhalation from a single cigarette and administration of test doses of nicotine. Complementing this approach are studies (1) in which receptor antagonists are administered in an attempt to explore putative transmitter systems regulating the acute smoking-induced electroencephalographic response and (2) in which electroencephalographic profiles of acute smoking are compared with electroencephalographic profiles resulting from administration of single doses of psychotropic substances. Completing these studies are attempts to monitor the electrocortical correlates of repeated smoking exposure and smoking deprivation, which, together with investigations examining smoker vs. nonsmoker differences and the effects of chronic life-long smoking, provide objective insights into the neuroelectrophysiology underlying the smoking habit.

EEG alpha correlates of alcohol consumption in smokers and nonsmokers. Effects of smoking and smoking deprivation.

Tobacco smoking either prior to or during alcohol consumption or both counteracted the alcohol-induced slowing of alpha frequency which was evident in both nonsmokers and deprived smokers.

Noise and task induced distraction effects on information processing: sex differences in smokers and non-smokers.

Choice reaction time performance was monitored in male and female smokers and nonsmokers during the separate and combined presentation of noise- and task-induced distraction. Behavioral measures of decision time and movement time were examined together with response errors. Relative to female nonsmokers, female smokers exhibited significantly slower decision times during both separate and combined presentation of distractors. Female smokers also showed significantly longer decision times than male smokers during task-induced distraction. Significant differences were also observed with response errors, with task and combined noise- and task-induced distraction resulting in greater impairment in female smokers. The results are supportive of a relative central information processing deficit in female smokers and discussion is focused on the role of attentional processes.

Electrodermal activity during aversive stimulation: sex differences in smokers and non-smokers.

Skin conductance activity was monitored in male and female smokers and non-smokers during repeated presentation of high intensity auditory stimuli. Smokers, and, in particular, female smokers, exhibited significantly higher resting skin conductance levels and significantly larger skin conductance responses. The results are discussed in relation to "stress-reduction" smoking.

Acute effects of tobacco on human brain stem evoked potentials.

Reports of tobacco-induced electrocortical activation have frequently indicated that this effect is mediated via nicotine's action on sub-cortical structures. This study focused on human brain stem involvement by examining the acute effects of tobacco smoking on brain stem auditory potentials (BSAEPs). Twelve regular smokers were tested on two separate sessions involving sham or real smoking. On each session, BSAEPs were recorded during a baseline period and immediately after smoking. BSAEPs, recorded from Cz, were elicited by presentation of 1,000 monaural, rare fraction click stimuli. Latency and amplitudes of peak components I, III and V were assessed and analysed. No significant effects were observed for latency measures or for amplitudes of peaks I and III. A significant effect was observed for peak V with tobacco resulting in larger amplitudes relative to sham smoking. Peak V reflects activity from upper pontine-lower midbrain sites and this tobacco-peak V finding is discussed in relation to arousal and information processing theories of smoking.