Fatigue and brain arousal in patients with major depressive disorder.

Fatigue is considered a key symptom of major depressive disorder (MDD), yet the term lacks specificity. It can denote a state of increased sleepiness and lack of drive (i.e., downregulated arousal) as well as a state of high inner tension and inhibition of drive with long sleep onset latencies (i.e., upregulated arousal), the latter typically found in depression. It has been proposed to differentiate fatigue along the dimension of brain arousal. We investigated whether such stratification within a group of MDD patients would reveal a subgroup with distinct clinical features. Using an automatic classification of EEG vigilance stages, an arousal stability score was calculated for 15-min resting EEGs of 102 MDD patients with fatigue. 23.5% of the patients showed signs of hypoarousal with EEG patterns indicating drowsiness or sleep; this hypoaroused subgroup was compared with remaining patients (non-hypoaroused subgroup) concerning self-rated measures of depressive symptoms, sleepiness, and sleep. The hypoaroused subgroup scored higher on the Beck Depression Inventory items "loss of energy" (Z = - 2.13, p = 0.033; ɳ2 = 0.044, 90% CI 0.003-0.128) and "concentration difficulty" (Z = - 2.40, p = 0.017; ɳ2 = 0.056, 90% CI 0.009-0.139), and reported higher trait and state sleepiness (p < 0.05) as compared to the non-hypoaroused group. The non-hypoaroused subgroup, in contrast, reported more frequently the presence of suicidal ideation (Chi2 = 3.81, p = 0.051; ɳ2 = 0.037, 90% CI 0.0008-0.126). In this study, we found some evidence that stratifying fatigued MDD patients by arousal may lead to subgroups that are pathophysiologically and clinically more homogeneous. Brain arousal may be a worth while target in clinical research for better understanding the mechanisms underlying suicidal tendencies and to improve treatment response.

Brain arousal regulation and depressive symptomatology in adults with attention-deficit/hyperactivity disorder (ADHD).

BACKGROUND: The aim of the present study was to evaluate the stability of brain arousal in adult attention-deficit/hyperactivity disorder (ADHD) outpatients with and without depressive symptomatology, and its association with depressive symptom severity and absolute electroencephalogram (EEG) power in different frequency bands. METHODS: We included 31 outpatient adults (45.16% females), who were diagnosed according to DSM-IV and received no medication. Their arousal stability score (index of the steepness of arousal decline during a 15-min EEG under resting conditions), the absolute EEG power and self-reports, including depressive and ADHD-related symptoms, were analyzed. Participants were split into an unstable and stable arousal group based on the median (= 6) of the arousal stability score. RESULTS: ADHD patients in the stable group reported more severe depressive symptoms (p = 0.018) and showed reduced absolute EEG power in the delta (0.002 ≤ p ≤ 0.025) and theta (0.011 ≤ p ≤ 0.034) bands compared to those in the unstable group. There was no correlation between the arousal stability score and self-report-scales concerning ADHD-related symptoms (0.214 ≤ p ≤ 0.989), but a positive association with self-reported depressive severity (p = 0.018) and negative association with powers in the EEG delta and theta bands (0.001 ≤ p ≤ 0.033). CONCLUSIONS: In view of high comorbidity of depression and ADHD in adult patients, these findings support the assumption that brain arousal regulation could be considered as a helpful marker for the clinical differentiation between ADHD and depression.

Impact of brain arousal and time-on-task on autonomic nervous system activity in the wake-sleep transition.

BACKGROUND: Autonomic nervous system (ANS) activity has been shown to vary with the state of brain arousal. In a previous study, this association of ANS activity with distinct states of brain arousal was demonstrated using 15-min EEG data, but without directly controlling for possible time-on-task effects. In the current study we examine ANS-activity in fine-graded EEG-vigilance stages (indicating states of brain arousal) during two conditions of a 2-h oddball task while controlling for time-on-task. In addition, we analyze the effect of time-on-task on ANS-activity while holding the level of brain arousal constant. METHODS: Heart rate and skin conductance level of healthy participants were recorded during a 2-h EEG with eyes closed under simultaneous presentation of stimuli in an ignored (N = 39) and attended (N = 39) oddball condition. EEG-vigilance stages were classified using the Vigilance Algorithm Leipzig (VIGALL 2.1). The time-on-task effect was tested by dividing the EEG into four 30-min consecutive time blocks. ANS-activity was compared between EEG-vigilance stages across the entire 2 h and within each time block. RESULTS: We found a coherent decline of ANS-activity with declining brain arousal states, over the 2-h recording and in most cases within each 30-min block in both conditions. Furthermore, we found a significant time-on-task effect on heart rate, even when arousal was kept constant. It was most pronounced between the first and all subsequent blocks and could have been a consequence of postural change at the beginning of the experiment. CONCLUSION: Our findings contribute to the validation of VIGALL 2.1 using ANS parameters in 2-h EEG recording under oddball conditions.

Evoked potentials and behavioral performance during different states of brain arousal.

BACKGROUND: Previous studies compared evoked potentials (EPs) between several sleep stages but only one uniform wake state. However, using electroencephalography (EEG), several arousal states can be distinguished before sleep onset. Recently, the Vigilance Algorithm Leipzig (VIGALL 2.0) has been developed, which automatically attributes one out of seven EEG-vigilance stages to each 1-s EEG segment, ranging from stage 0 (associated with cognitively active wakefulness), to stages A1, A2 and A3 (associated with relaxed wakefulness), to stages B1 and B2/3 (associated with drowsiness) up to stage C (indicating sleep onset). Applying VIGALL, we specified the effects of these finely differentiated EEG-vigilance stages (indicating arousal states) on EPs (P1, N1, P2, N300, MMN and P3) and behavioral performance. Subjects underwent an ignored and attended condition of a 2-h eyes-closed oddball-task. Final analysis included 43 subjects in the ignored and 51 subjects in the attended condition. First, the effect of brain arousal states on EPs and performance parameters were analyzed between EEG-vigilance stages A (i.e. A1, A2 and A3 combined), B1 and B2/3&C (i.e. B2/3 and C combined). Then, in a second step, the effects of the finely differentiated EEG-vigilance stages were further specified. RESULTS: Comparing stages A versus B1 versus B2/3&C, a significant effect of EEG-vigilance stages on all behavioral parameters and all EPs, with exception of MMN and P3, was found. By applying VIGALL, a more detailed view of arousal effects on EP and performance was possible, such as the finding that the P2 showed no further significant increase in stages deeper than B1. Stage 0 did not differ from any of the A-stages. Within more fine-graded stages, such as the A-substages, EPs and performance only partially differed. However, these analyses were partly based on small sample sizes and future studies should take effort to get enough epochs of rare stages (such as A3 and C). CONCLUSIONS: A clear impact of arousal on EPs and behavioral performance was obtained, which emphasize the necessity to consider arousal effects when interpreting EPs.

Why do stimulants not work in typical depression?

Stimulants have been suggested as therapeutics in depression for 80 years now, but there is still no evidence from randomized controlled trials that stimulants, in general, possess specific antidepressant effects. Also, several recent large randomized controlled trials which tried to establish an indication for stimulants as add-on in depression failed, and the companies no longer proceed with regulatory filings. One reason why the common belief of an antidepressant effect has survived over decades is a lack of clarity in psychopathology. Tiredness in the sense of sleepiness (downregulation of arousal) and lack of drive are mixed up with tiredness in the sense of exhaustion with high inner tension (upregulation of arousal) and inhibition of drive. The latter is found in typical depression, and according to the recently introduced arousal regulation model of affective disorders, upregulation of arousal is considered to be an important pathogenetic factor. Psychostimulants are unlikely to have beneficial effects in those patients with upregulated arousal. However, there might be subgroups of depressed patients, such as atypical depression, which suffer from sleepiness and lack of drive and might respond to stimulants. Arousal, a dimension included in the Research Domain Criteria project of the National Institute of Mental Health, can be assessed with an electroencephalography-based algorithm (the Vigilance Algorithm Leipzig) and is a promising biomarker to identify subgroups of patients, which might respond to stimulants.

Early report on brain arousal regulation in manic vs depressive episodes in bipolar disorder.

OBJECTIVES: The arousal regulation model of affective disorders attributes an important role in the pathophysiology of affective disorders to dysregulation of brain arousal regulation. According to this model, sensation avoidance and withdrawal in depression and sensation seeking and hyperactivity in mania can be explained as auto-regulatory attempts to counteract a tonically high (depression) or unstable (mania) arousal. The aim of this study was to compare brain arousal regulation between manic and depressive bipolar patients and healthy controls. We hypothesized that currently depressed patients with bipolar disorder show hyperstable arousal regulation, while currently manic patients show unstable arousal regulation. METHODS: Twenty-eight patients with bipolar disorder received a 15-min resting electroencephalogram (EEG) during a depressive episode and 19 patients received the same during a manic/hypomanic episode. Twenty-eight healthy control subjects were matched for age and sex. The Vigilance Algorithm Leipzig (VIGALL), which classifies 1-s EEG segments as one of seven EEG-vigilance substages, was used to measure brain arousal regulation. RESULTS: Manic patients showed more unstable EEG-vigilance regulation as compared to the control sample (P = .004) and to patients with a depressive episode (P ≤ .001). Depressive patients had significantly higher mean vigilance levels (P = .045) than controls. CONCLUSIONS: A clear difference was found in the regulation of brain arousal of manic patients vs depressive patients and controls. These data suggest that brain arousal might depend on the current mood state, which would support the arousal regulation model of affective disorders.

Stochastic resonance is not required for pink noise to have beneficial effects on ADHD-related performance? The moderate brain arousal model challenged.

OBJECTIVE: Random noise, such as white or pink noise, has been shown to have beneficial effects on the performance of individuals with (elevated traits of) ADHD. Both the state regulation deficit (SRD) account and the moderate brain arousal (MBA) model argue that this effect is due to enhanced cognitive arousal. The MBA model specifically attributes this to random noise affecting dopaminergic (DA) transmission via stochastic resonance (SR). However, he requirement of SR and the role of DA have not yet been properly examined. To test this, proper control conditions are needed. METHOD: To examine the requirement of SR, 60 neurotypical adults with varying levels of ADHD traits performed a slow two-choice reaction time (S1-S2) task in three auditory conditions: pink (random) noise, a pure 100 Hz tone (non-random noise), and silence. All participants also completed the Attention Network Test (ANT) in two conditions (pink noise and silence) to inspect the effect on executive network efficiency which may serve as a proxy measure of DA. ADHD traits were assessed via self-report. RESULTS: Auditory stimulation improved performance on the S1-S2 task in participants with elevated ADHD traits, however this was the case for both pink noise and the pure tone. Pink noise did not affect executive network efficiency, irrespective of ADHD traits. CONCLUSIONS: Our results suggest that stochastic resonance is not required for pink noise to have a beneficial effect on ADHD-related performance. Pink noise did not affect our DA proxy measure, however this negative finding should be interpreted with caution. Our results cast doubt on the tenets of the MBA model, warranting further research.

The impact of emotional dysregulation and comorbid depressive symptoms on clinical features, brain arousal, and treatment response in adults with ADHD.

Introduction: The role of emotional dysregulation (ED) in attention-deficit/hyperactivity disorder (ADHD) has become an important issue. This study, in which we analyzed data from a predictive pharmaco-EEG-trial, aimed to examine whether symptoms of ED in adult ADHD affect ADHD symptom severity, brain arousal regulation as measured by resting EEG, and the response to stimulant medication. Methods: ED is defined as having a sex- and age-corrected T-score of >70 on the emotional lability subscale of the German version of Conners' Adult ADHD Rating Scale. A total of 115 participants were included in the study, 56 of whom had ED. Participants with ED were more impaired in terms of the severity of core ADHD symptoms, especially inattentive symptoms, comorbid depressive symptoms, interpersonal relationships, and quality of life. In addition, participants with ED were more likely to report a total score above 13 on the Beck Depression Inventory-II, which was considered to be the cutoff for mild depression. Results: No differences were found between the ED and non-ED groups in response to stimulant medication or in brain arousal regulation. In addition, there was no significant effect of ED with comorbid depressive symptoms on treatment response. There was a trend for subgroups that showed a change in brain arousal regulation associated with symptom improvement. Discussion: Our findings may support the assumption that ED may be an important feature of ADHD. The use of EEG-based brain arousal regulation as a diagnostic and predictive tool in ADHD in the presence of ED and comorbid depressive symptoms should be further investigated.

Listening to White Noise Improved Verbal Working Memory in Children with Attention-Deficit/Hyperactivity Disorder: A Pilot Study.

Existing research demonstrates that children with attention-deficit/hyperactivity disorder (ADHD) underperform in cognitive tasks involving working memory (WM) due to hypo-arousal, which has led to the development of arousal regulation models to determine proper levels of arousal and optimal cognitive outcomes. The present study focuses on investigating the effects of external auditory stimuli on verbal WM in children with ADHD. Thirteen children with ADHD (aged 6-10 years old) and thirteen age- and gender-matched children with typical development (TD) completed the verbal WM task when listening to no sound, white noise, or pleasant music. A two-way repeated-measures analysis of variance was used to compare the verbal WM performance between groups in the three auditory conditions. Children with ADHD showed the best verbal WM performance when listening to white noise and the worst performance when listening to no sound. Yet, children with TD performed the best in the no-sound condition and the worst in the white noise condition. Our findings suggest auditory white noise is beneficial for ideal arousal regulation and cognitive performance involving verbal WM for children with ADHD and support the moderate brain arousal model. Providing external white noise is a non-invasive and cost-effective approach to improving verbal WM in children with ADHD in real-world contexts.

Event rate effects on children with attention-deficit/hyperactive disorder: Test predictions from the moderate brain arousal model and the neuro-energetics theory using the diffusion decision model.

BACKGROUND: Converging evidence has found that the inhibitory control of children with attention-deficit/hyperactive disorder (ADHD) is context-dependent and particularly susceptible to the event rate. The Moderate Brain Arousal (MBA) model predicts a U-shaped curve between event rate and performance as a modulation of brain arousal. The neuroenergetics theory (NeT) proposes that a smaller event rate results in neuronal fatigue and subsequent descent performance. However, previous work applied the traditional one-dimensional index of performance, such as accuracy rate and response time, which might limit the exploration of the event rate effect on the specific underlying process. AIMS: We used a diffusion decision model (DDM) to study the influence of event rate on inhibition control in children with ADHD and verified the explanation of the MBA model and the NeT. METHODS AND PROCEDURES: The Stop Signal Task manipulated by four event rate conditions was conducted with 24 children with ADHD (mean age=8.5, males=16) and 29 typical developmental children (TDC) (mean age=9.0, males=12). DDM was applied to compare the differences in the DDM parameters across different event rates. OUTCOMES AND RESULTS: Compared with TDC, children with ADHD had a smaller drift rate, longer non-decision time, and smaller boundary separation. Although the event rate had little influence on ADHD, the drift rate of the TDC was approximately linear with an increased event rate, and the Ter had a quadratic function relationship with the event rate. CONCLUSIONS AND IMPLICATIONS: The event rate effect may influence children's performance through dual mechanisms. Neuronal energy supply could regulate information processing and brain arousal to regulate the activation of primary stimuli encoding and motor control. Insight into the multi-mechanism of ADHD cognition deficits would be helpful for clinicians in making objective diagnoses and effective targeted treatments.

Brain Arousal as Measured by EEG-Assessment Differs Between Children and Adolescents With Attention-Deficit/Hyperactivity Disorder (ADHD) and Depression.

Objective: Disturbed regulation of vigilance in the wake state seems to play a key role in the development of mental disorders. It is assumed that hyperactivity in adult ADHD is an attempt to increase a general low vigilance level via external stimulation in order to avoid drowsiness. For depression, the avoidance of stimulation is interpreted as a reaction to a tonic increased vigilance state. Although ADHD is assumed to start during childhood, this vigilance model has been barely tested with children diagnosed for ADHD so far. Methods: Resting-state EEG (8 min) measures from two groups of children diagnosed with either ADHD [N = 76 (16 female, 60 male), age: (mean/SD) 118/33 months] or depression [N = 94 (73 female, 21 male), age: 184/23 months] were analyzed. Using the VIGALL toolbox, EEG patterns of vigilance level, and regulation were derived and compared between both groups. In correlation analysis, the relations between vigilance measures, attentional test performance (alertness and inhibition), and mental health symptoms were analyzed. Results: Children with ADHD differed from children with most prominent depressive symptoms in brain arousal regulation and level, but EEG vigilance was not related to behavior problems and not related to the attentional test performance. Brain arousal was dependent on the age of the participant in the whole sample; younger children showed lower vigilance stages than teenagers; this effect was not present when analyzed separately for each diagnostic group. EEG assessment time and received medication had no effect on the EEG vigilance. Discussion: Although based on a small sample, this explorative research revealed that EEG vigilance level is different between children with ADHD and with depression. Moreover, even the standard procedure of the clinical routine EEG (resting state) can be used to differentiate brain arousal states between participants with ADHD and depression. Because routine EEG is not specialized to vigilance assessment, it may not be sufficiently sensitive to find vigilance-symptomatology associations. Further research should address developmental changes in EEG measurements in children and use bigger samples of participants within the same age range.

The "VIP-ADHD trial": Does brain arousal have prognostic value for predicting response to psychostimulants in adult ADHD patients?

EEG studies have shown that adult ADHD patients have less stable brain arousal regulation than age and gender matched controls. Psychostimulants have brain arousal stabilising properties evident in EEG patterns. The aim of this study was to investigate whether the stability of brain arousal regulation has prognostic value in predicting response to methylphenidate therapy in adult ADHD patients. In an open-label, single-arm, multi-centre, confirmatory trial, 121 adult ADHD patients were recruited and 112 qualified for the full analysis set. All participants received an initial dose of 20 mg extended release methylphenidate at baseline. After a titration phase of up to 4 weeks, patients remained on a weight-based target dose of extended release methylphenidate for 4 weeks. Using the Vigilance Algorithm Leipzig (VIGALL 2.1), we assessed brain arousal regulation before the treatment with methylphenidate, based on a 15-min EEG at quiet rest recorded at baseline. Using automatic stage-classification of 1 s segments, we computed the mean EEG-vigilance (indexing arousal level) and an arousal stability score (indexing arousal regulation). The primary endpoint was the association between successful therapy, defined by a 30% reduction in CAARS, and stable/unstable brain arousal. 52 patients (46%) showed an unstable brain arousal regulation of which 23% had therapy success. In the stable group, 35% had therapy success, implying an absolute difference of 12 percentage points (95% CI -5 to 29, p = 0.17) in the direction opposite to the hypothesized one. There were no new findings regarding the tolerability and safety of extended release methylphenidate therapy.

Brain arousal regulation in SSRI-medicated patients with major depression.

EEG measures of arousal have been suggested as diagnostic and predictive biomarkers for major depression. The aim of the present study was to examine whether self-rated depression severity in SSRI-medicated patients with major depression (MD) is associated with EEG measures of brain arousal. Based on previous studies, we expected that a higher level of brain arousal and a slower arousal decline during a 15-min EEG recording are associated with higher symptom severity as assessed with the Beck Depression Inventory (BDI) at the time of the EEG recording. EEGs of 78 MD patients and 46 healthy controls were analyzed. Brain arousal was assessed using the Vigilance Algorithm Leipzig (VIGALL 2.1). Based on automatically classified 1-s segments (EEG-vigilance Stages 0, A1, A2, A3, B1, B2/3 or C) we computed indices to assess the level (mean EEG-vigilance) and the decline of arousal (slope index) during the 15-min resting state EEG under eyes-closed condition. We found that a higher arousal level and a slower arousal decline corresponded to higher severity of depressive symptoms (rho = 0.238, p = .018; and rho = 0.236; p = .019). Self-rated non-remitters (BDI>12) had a higher arousal level (mean EEG-vigilance: t76 = -2.19, p = .016) and slower arousal decline (slope index: Z = -2.08, p = .019) during the 15-min recording as compared to remitters. Similar results were obtained between non-remitters and healthy controls (mean EEG-vigilance: t102 = -2.75, p = .004; slope index: Z = -1.92, p = .028), but not between remitters and controls (p > .260). The findings support the model that brain arousal regulation plays an important role in the pathophysiology and treatment of MD.

Resting EEG Measures of Brain Arousal in a Multisite Study of Major Depression.

Several studies have found upregulated brain arousal during 15-minute EEG recordings at rest in depressed patients. However, studies based on shorter EEG recording intervals are lacking. Here we aimed to compare measures of brain arousal obtained from 2-minute EEGs at rest under eyes-closed condition in depressed patients and healthy controls in a multisite project-Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care (EMBARC). We expected that depressed patients would show stable and elevated brain arousal relative to controls. Eighty-seven depressed patients and 36 healthy controls from four research sites in the United States were included in the analyses. The Vigilance Algorithm Leipzig (VIGALL) was used for the fully automatic classification of EEG-vigilance stages (indicating arousal states) of 1-second EEG segments; VIGALL-derived measures of brain arousal were calculated. We found that depressed patients scored higher on arousal stability ( Z = -2.163, P = .015) and A stages (dominant alpha activity; P = .027) but lower on B1 stages (low-voltage non-alpha activity, P = .008) compared with healthy controls. No significant group differences were observed in Stage B2/3. In summary, we were able to demonstrate stable and elevated brain arousal during brief 2-minute recordings at rest in depressed patients. Results set the stage for examining the value of these measures for predicting clinical response to antidepressants in the entire EMBARC sample and evaluating whether an upregulated brain arousal is particularly characteristic for responders to antidepressants.

Defining the Construct of Synthetic Androgen Intoxication: An Application of General Brain Arousal.

Synthetic androgens (i. e., anabolic-androgenic steroids) are the primary component to the majority of problematic appearance and performance enhancing drug (APED) use. Despite evidence that these substances are associated with increased risk for aggression, violence, body image disturbances, and polypharmacy and can develop a pattern of chronic use consistent with drug dependence, there are no formal definitions of androgen intoxication. Consequently, the purpose of this paper is to establish a testable theory of androgen intoxication. We present evidence and theorize that synthetic androgen intoxication can be defined by a pattern of poor self-regulation characterized by increased propensity for a range of behaviors (e.g., aggression, sex, drug seeking, exercise, etc.) via androgen mediated effects on general brain arousal. This theory posits that androgens reduce threshold for emotional reactivity, motor response, and alertness to sensory stimuli and disrupt inhibitory control over the behaviors associated with synthetic androgen use. These changes result from alteration to basic neurocircuitry that amplifies limbic activation and reduces top-down cortical control. The implications for this definition are to inform APED specific hypotheses about the behavioral and psychological effects of APED use and provide a basis for establishing clinical, legal, and public health guidelines to address the use and misuse of these substances.

Sleep disturbances and upregulation of brain arousal during daytime in depressed versus non-depressed elderly subjects.

OBJECTIVES: Although patients with depression often suffer from sleep disturbances, most of them are not sleepy. Upregulation of brain arousal has been proposed as pathophysiological mechanism explaining sleep disturbances, inner tension, autonomic hyperarousal and anhedonia in depression. The aim of the current study was to examine the association between night-time sleep disturbances and brain arousal regulation the next day in depressed versus non-depressed subjects. METHODS: Twenty-eight elderly subjects (21 female; age = 70.5 ± 4.4 years) with depressive syndromes without psychotropic medication, and 28 controls (22 female; age = 70.9 ± 4.5 years), underwent a 15-min resting electroencephalogram; the Vigilance Algorithm Leipzig (VIGALL 2.1) provided an objective measure of brain arousal regulation. Sleep disturbances were assessed by a validated and self-rated sleep questionnaire. RESULTS: In the depressive group, but not in controls, more sleep disturbances were associated with a higher brain arousal stability score (high score corresponds to upregulation) the next day (sleep onset latency: rs = 0.69, P < .0001; sleep quality: rs = -0.59, P < .001). CONCLUSIONS: The data confirm the hypothesis that in persons with depressive syndromes sleep disturbances are related to upregulation of brain arousal the next day. This finding is in line with the concept that dysregulation of brain arousal is a central pathophysiological aspect in depression.

Comparison of bNOS and chat immunohistochemistry in the laterodorsal tegmentum (LDT) and the pedunculopontine tegmentum (PPT) of the mouse from brain slices prepared for electrophysiology.

BACKGROUND: Identification of cell phenotype from brain slices upon which in vitro electrophysiological recordings have been performed often relies on conducting post hoc immunohistochemistry on tissue that necessarily has not been ideally prepared for immunohistochemical procedures. In such studies, antibody labeling against neuronal nitric oxide synthase (bNOS) has been used to identify cholinergic neurons of the laterodorsal tegmental nucleus (LDT) and the pedunculopontine tegmental nuclei (PPT), two brainstem nuclei importantly involved in arousal. However, a widespread perception maintains that antibody staining for enzymes involved in synthesis or transport, of acetylcholine would be a more definitive marker and hence, preferable. NEW METHOD: Colocalization of bNOS and CHAT in the LDT/PPT, and presence of parvalbumin (PV), was examined in non-ideally prepared mouse brain slices using currently available antibodies. RESULTS: Using fluorescent-based immunohistochemistry in LDT/PPT slices prepared for in vitro recordings, a near 100% colocalization of bNOS and CHAT was observed. COMPARISON WITH EXISTING METHOD: We confirm in the mouse, findings of near 100% colocalization of bNOS and CHAT in the LDT/PPT, and we expand upon data from rat studies using optimally prepared tissue, that for dendritic visualization, bNOS staining exceeded the quality of CHAT staining for visualization of a higher degree of detail of fine processes. PV is not highly present in the mouse LDT/PPT. CONCLUSION: CHAT and bNOS are equally useful target proteins for immunofluorescent identification of cholinergic LDT/PPT cells in mouse brain slices prepared for in vitro recordings, however, antibody targeting of bNOS allows for a superior appreciation of structural detail.

Fatigue with up- vs downregulated brain arousal should not be confused.

Fatigue is considered to be an important and frequent factor in motivation problems. However, this term lacks clinical and pathophysiological validity. Semantic precision has to be improved. Lack of drive and tiredness with increased sleepiness as observed in fatigue in the context of inflammatory and immunological processes (hypoaroused fatigue) has to be separated from inhibition of drive and tiredness with prolonged sleep onset latency as observed in major depression (hyperaroused fatigue). Subjective experiences as reported by patients, as well as clinical, behavioral, and neurobiological findings support the validity and importance of this distinction. A practical clinical procedure for how to separate hypo- from hyperaroused fatigue will be proposed.

Modelling ADHD: A review of ADHD theories through their predictions for computational models of decision-making and reinforcement learning.

Attention deficit hyperactivity disorder (ADHD) is characterized by altered decision-making (DM) and reinforcement learning (RL), for which competing theories propose alternative explanations. Computational modelling contributes to understanding DM and RL by integrating behavioural and neurobiological findings, and could elucidate pathogenic mechanisms behind ADHD. This review of neurobiological theories of ADHD describes predictions for the effect of ADHD on DM and RL as described by the drift-diffusion model of DM (DDM) and a basic RL model. Empirical studies employing these models are also reviewed. While theories often agree on how ADHD should be reflected in model parameters, each theory implies a unique combination of predictions. Empirical studies agree with the theories' assumptions of a lowered DDM drift rate in ADHD, while findings are less conclusive for boundary separation. The few studies employing RL models support a lower choice sensitivity in ADHD, but not an altered learning rate. The discussion outlines research areas for further theoretical refinement in the ADHD field.