Functional transcranial Doppler: Selection of methods for statistical analysis and representation of changes in flow velocity.

INTRODUCTION: Transcranial Doppler (TCD) is a method used to study cerebral hemodynamics. In the majority of TCD studies, regression analysis and analysis of variance are the most frequently applied statistical methods. However, due to the dynamic and interdependent nature of flow velocity, nonparametric tests may allow for better statistical analysis and representation of results. METHOD: The sample comprised 30 healthy participants, aged 33.87 ± 7.48 years; with 33% (n = 10) females. During a visuo-motor task, the mean flow velocity (MFV) in the middle cerebral artery (MCA) was measured using TCD. The MFV was converted to values relative to the resting state. The results obtained were analyzed using the general linear model (GLM) and the general additional model (GAM). The fit indices of both analysis methods were compared with each other. RESULTS: Both MCAs showed a steady increase in MFV during the visuo-motor task, smoothly returning to resting state values. During the first 20 seconds of the visuo-motor task, the MFV increased by a factor of 1.06 ± 0.07 in the right-MCA and by a factor of 1.08 ± 0.07 in the left-MCA. GLM and GAM showed a statistically significant change in MFV (GLM:F(2, 3598) = 16.76, P < .001; GAM:F(2, 3598) = 21.63, P < .001); together with effects of hemispheric side and gender (GLM:F(4, 3596) = 7.83, P < .005; GAM:F(4, 3596) = 2.13, P = .001). Comparing the models using the χ2 test for goodness of fit yields a significant difference χ2 (9.9556) = 0.6836, P < .001. CONCLUSIONS: Both the GLM and GAM yielded valid statistical models of MFV in the MCA in healthy subjects. However, the model using the GAM resulted in improved fit indices. The GAM's advantage becomes even clearer when the MFV curves are visualized; yielding a more realistic approach to brain hemodynamics, thus allowing for an improvement in the interpretation of the mathematical and statistical results. Our results demonstrate the utility of the GAM for the analysis and representation of hemodynamic parameters.

Psychopathological Symptom Load and Distinguishable Cerebral Blood Flow Velocity Patterns in Patients With Schizophrenia and Healthy Controls: A Functional Transcranial Doppler Study.

Introduction: Schizophrenia is a severe psychiatric disorder, with executive dysfunction and impaired processing speed playing a pivotal role in the course of the disease. In patients with schizophrenia, neurocognitive deficits appear to be related to alterations in cerebral hemodynamics. It is not fully understood if psychopathological symptom load (i.e., presence and severity of symptoms) is also related to alterations in cerebral hemodynamics. We aim to study the relationship between psychopathological symptom load and cerebral hemodynamics in the Middle Cerebral Artery (MCA) during a cognitive task in patients with schizophrenia and healthy controls. Methodology: Cerebral hemodynamics in the MCA were examined in 30 patients with schizophrenia and 15 healthy controls using functional Transcranial Doppler (fTCD) during the Trail Making Test (TMT). Psychopathological symptoms were measured using the Brief Psychiatric Rating Scale (BPRS). Patients were dichotomized according to BPRS scores: mild-moderate (BPRS < 41, n = 15) or marked-severe (BPRS ≧ 41, n = 15). Mean blood flow velocity (MFV) in the MCA and processing speed of the TMT were analyzed. Cerebral hemodynamics were analyzed using the general additional model (GAM) with a covariate analysis of variance (ANCOVA) for group comparisons. Results: Patients and healthy controls were comparable regarding demographics. Patients had a slower processing speed for the TMT-A (patients-severe: 52s, patients-moderate: 40s, healthy-controls: 32s, p = 0.019) and TMT-B [patients-severe: 111s, patients-moderate: 76s, healthy-controls: 66s, p < 0.001)]. Patients demonstrated differing hemodynamic profiles in both TMTs: TMT- A [F (6, 1,792) = 17, p < 0.000); TMT-B [F (6, 2,692) = 61.93, p < 0.000], with a delay in increase in MFV and a failure to return to baseline values. Conclusions: Patients with schizophrenia demonstrated slower speeds of processing during both the TMT-A and TMT-B. The speed of processing deteriorated with increasing psychopathological symptom load, additionally a distinct cerebral hemodynamic pattern in the MCA was observed. Our results further support the view that severity of schizophrenia, particularly psychopathological symptom load, influences performance in neurocognitive tasks and is related to distinct patterns of brain hemodynamics.

Correction: Cerebral blood flow variability in fibromyalgia syndrome: Relationships with emotional, clinical and functional variables.

[This corrects the article DOI: 10.1371/journal.pone.0204267.].

Cerebral blood flow variability in fibromyalgia syndrome: Relationships with emotional, clinical and functional variables.

OBJECTIVE: This study analyzed variability in cerebral blood flow velocity (CBFV) and its association with emotional, clinical and functional variables and medication use in fibromyalgia syndrome (FMS). METHODS: Using transcranial Doppler sonography, CBFV were bilaterally recorded in the anterior (ACA) and middle (MCA) cerebral arteries of 44 FMS patients and 31 healthy individuals during a 5-min resting period. Participants also completed questionnaires assessing pain, fatigue, insomnia, anxiety, depression and health-related quality of life (HRQoL). RESULTS: Fast Fourier transformation revealed a spectral profile with four components: (1) a first very low frequency (VLF) component with the highest amplitude at 0.0024 Hz; (2) a second VLF component around 0.01-to-0.025 Hz; (3) a low frequency (LF) component from 0.075-to-0.11 Hz; and (4) a high frequency (HF) component with the lowest amplitude from 0.25-to-0.35 Hz. Compared to controls, FMS patients exhibited lower LF and HF CBFV variability in the MCAs (p < .005) and right ACA (p = .03), but higher variability at the first right MCA (p = .04) and left ACA (p = .005) VLF components. Emotional, clinical and functional variables were inversely related to LF and HF CBFV variability (r≥-.24, p≤.05). However, associations for the first VLF component were positive (r≥.28, p≤.05). While patients´ medication use was associated with lower CBFV variability, comorbid depression and anxiety disorders were unrelated to variability. CONCLUSIONS: Lower CBFV variability in the LF and HF ranges were observed in FMS, suggesting impaired coordination of cerebral regulatory systems. CBFV variability was differentially associated with clinical variables as a function of time-scale, with short-term variability being related to better clinical outcomes. CBFV variability analysis may be a promising tool to characterize FMS pathology and it impact on facets of HRQoL.

Cerebral blood flow modulations during preparatory attention and proactive inhibition.

This study investigated cerebral blood flow modulations during task preparation in a precued saccade paradigm. Bilateral blood flow velocities in the middle cerebral arteries were recorded in 48 subjects using functional transcranial Doppler sonography. Video-based eye-tracking was applied for ocular recording. Antisaccade and prosaccade trials were presented in both block-wise and interleaved order. A right dominant flow response arose during task preparation. While the response was stronger during antisaccade than prosaccade trials, the degree of lateralisation did not differ between the two trial types. Direction error rates were higher and latencies were longer for antisaccades than prosaccades. There were no differences between block-wise and interleaved trials in blood flow or performance. The stronger blood flow increases during antisaccade than prosaccade preparation reflects the complexity of the upcoming task demands as well as proactive inhibition. The right hemispheric lateralisation may be attributed to preparatory attention independent of demands on inhibitory control.

Extrapyramidal symptoms in schizophrenia: evidence of blunted cerebral hemodynamics during a planning task.

Acute extrapyramidal symptoms (EPS) occur frequently in schizophrenia, mostly caused by antidopaminergic substances. There have been no published reports on the impact of acute EPS on cerebral blood flow (CBF) or related measures. In the following study, we examined schizophrenic patients with and without EPS during a planning task and measurements of CBF velocity. Sixteen patients with chronic schizophrenia and 16 healthy participants performed a planning paradigm during bilateral functional transcranial Doppler sonography of the middle cerebral arteries. Patients with acute EPS showed blunted CBF velocity exclusively during difficult planning tasks, and correlation analyses confirmed that higher EPS scores were associated with reduced adaption of CBF velocity. EPS in schizophrenia are associated with a detrimental effect on CBF velocity. Hypothetically, compromised adaptation of cerebral hemodynamics during difficult, but not during easy planning tasks is one correlate of dysfunctional frontostriatal circuits in schizophrenic patients with EPS.

Switching from oral atypical antipsychotic monotherapy to paliperidone palmitate once-monthly in non-acute patients with schizophrenia: A prospective, open-label, interventional study.

RATIONALE: Long-acting injectable antipsychotic therapies may offer benefits over oral antipsychotics in patients with schizophrenia. OBJECTIVE: This study aimed to explore the safety, tolerability, and treatment response of paliperidone palmitate once-monthly in non-acute but symptomatic adult patients switched from previously unsuccessful monotherapy with frequently used oral atypical antipsychotics. METHODS: This was a post hoc analysis of a prospective, interventional, single-arm, international, multicenter, open-label, 6-month study. RESULTS: The patients (N = 472) were switched to paliperidone palmitate once-monthly (PP1M) from daily oral treatment with either aripiprazole (n = 46), olanzapine (n = 87), paliperidone extended-release (n = 104), quetiapine (n = 44), or risperidone (n = 191). In all groups, mean Positive and Negative Syndrome Scale total (p < 0.0001) and Clinical Global Impression-Severity scores improved significantly (p = 0.0004 to p < 0.0001). An improvement of ≥50 % in the Positive and Negative Syndrome Scale total score was observed in 21.7 % (aripiprazole), 29.9 % (olanzapine), 29.8 % (paliperidone extended-release), 27.3 % (quetiapine), and 37.2 % (risperidone) of patients. The patients showed significant improvements in the Personal and Social Performance score (aripiprazole p = 0.0409, all others p ≤ 0.0015); Mini International Classification of Functionality, Disability and Health Rating for Activity and Participation Disorders in Psychological Illnesses total scores (all p < 0.01); and Treatment Satisfaction Questionnaire for Medication Global Satisfaction score (olanzapine and risperidone p < 0.0001, quetiapine p = 0.0465, paliperidone extended-release p = 0.0571, aripiprazole p = NS). Paliperidone palmitate once-monthly was well tolerated, presenting no new safety signals. CONCLUSIONS: These data illustrate that stable, non-acute but symptomatic patients on oral antipsychotic monotherapy may show clinically meaningful improvement of symptoms, functioning, and treatment satisfaction after direct transition to PP1M. The findings are limited by the naturalistic study design; thus, further studies are required to confirm the current findings.

Determinants of cerebral hemodynamics during the Trail Making Test in schizophrenia.

Patients with schizophrenia show deficits in cognitive functioning, and studies on cerebral hemodynamics have revealed aberrant patterns of mean cerebral blood flow velocity (MFV), an equivalent of cerebral blood flow (CBF). Therefore, we carried out a controlled study that assessed MFV in schizophrenia during a well-known neuropsychological task, the Trail Making Test (TMT). We measured MFV in the middle cerebral arteries using functional transcranial Doppler sonography in 15 schizophrenia patients and 15 healthy subjects. In comparison to healthy subjects, patients performed poorer on the TMT-A and the TMT-B, and there was increased cerebral blood flow velocity during the TMT-B. A comparison of subgroups of patients and controls matched in performance on the TMT-B revealed that these patients still showed significantly increased cerebral blood flow velocity. Increased MFV in schizophrenia suggests specific alterations of cerebral hemodynamics during the Trail Making Test, Part B, which are not detectable during visuomotor activity, and which are independent of performance. These findings emphasize the pathophysiological importance of cognitive functioning in schizophrenia, but cast doubts whether performance in this particular test plays a relevant role for CBF abnormalities in schizophrenia.

Combined symptomatology of psychosis, pica syndrome, and hippocampal sclerosis: a case report.

Pica is the developmentally and culturally inappropriate eating of nonnutritive substances for at least 1 month. Herein, we present the case of a male patient that suddenly showed behavioral changes including aggressiveness, withdrawal, and perceptional disturbances at the age of 12. About 7 years later, pica symptoms emerged additionally. Neither pharmacotherapy nor electroconvulsive therapy led to success. Magnetic resonance imaging showed bilateral sclerosis of the hippocampus. The therapy with carbamazepine, clozapine, diazepam, and zinc finally improved the symptoms including the pica symptoms.

Cerebral blood flow dynamics during pain processing in patients with fibromyalgia syndrome.

OBJECTIVES: Increased cerebral blood flow during processing of acute pain has repeatedly been observed in fibromyalgia syndrome. The study investigated the time dynamics of the pain-related hemodynamic response in fibromyalgia using transcranial Doppler sonography. METHODS: In 25 women with fibromyalgia and 25 healthy participants, blood flow velocities in the anterior and middle cerebral arteries of both hemispheres were recorded, while heat stimuli of 45°C were applied to their forearms. Thermal pain threshold and subjective pain experience during stimulation were assessed, and the participants completed the McGill Pain Inventory, Beck Depression Inventory, and State-Trait Anxiety Inventory. RESULTS: The early component of the blood flow response in both anterior cerebral arteries, that is, the steep flow increase during the initial stimulation period, was more pronounced in the patients than in the controls (mean [standard deviation] = 1.28% [1.85%] versus 0.24% [1.58%], p = .04). The patients showed lower pain threshold (p = .018), stronger sensory and affective pain experience (p < .001), and increased values on all questionnaire scales (all p values < .001). Although higher scores on each of the scales were associated with a stronger early blood flow response (r values ranging from 0.17 to 0.36), clinical pain severity proved to be the best predictor (ß = .33, p = .02). CONCLUSIONS: The increased blood flow response in the anterior cerebral arteries reflects hyperactivity of medial structures of the neuromatrix of nociception, structures involved in the processing of affective and cognitive aspects of pain. Aberrances in cerebral blood flow related to fibromyalgia and its clinical characteristics become particularly apparent in the enhancement of the initial component of the hemodynamic response.

Gender and rapid alterations of hemispheric dominance during planning.

BACKGROUND: Mental planning and carrying out a plan provoke specific cerebral hemodynamic responses. Gender aspects of hemispheric laterality using rapid cerebral hemodynamics have not been reported. METHOD: Here, we applied functional transcranial Doppler sonography to examine lateralization of cerebral hemodynamics of the middle cerebral arteries of 28 subjects (14 women and 14 men) performing a standard planning task. There were easy and difficult problems, and mental planning without motor activity was separated from movement execution. RESULTS: Difficult mental planning elicited lateralization to the right hemisphere after 2 or more seconds, a feature that was not observed during movement execution. In females, there was a dominance to the left hemisphere during movement execution. Optimized problem solving yielded an increased laterality change to the right during mental planning. CONCLUSIONS: Gender-related hemispheric dominance appears to be condition-dependent, and change of laterality to the right may play a role in optimized performance. Results are of relevance when considering laterality from a perspective of performance enhancement of higher cognitive functions, and also of psychiatric disorders with cognitive dysfunctions and abnormal lateralization patterns such as schizophrenia.

Sustained cognitive impairments after clinical recovery of severe depression.

Neuropsychological impairment is prominent in patients with depression, but it is unclear whether deficits persist after clinical response. This study aimed to investigate neuropsychological functions in the course of the illness. Depressive patients were investigated in the acute state and after clinical response using an extensive neuropsychological test battery. After clinical response, there was only a partial improvement in learning and memory and there were no changes regarding working memory, executive functions, and attention. Transient impairments in visual learning and memory suggest a depression-related state effect. The continuing deficits in attention, working memory, and executive function might be considered a trait marker.

Gender characteristics of cerebral hemodynamics during complex cognitive functioning.

Functional Transcranial Doppler sonography (fTCD) has been applied to assess peak mean cerebral blood flow velocity (MFV) with a high temporal resolution during cognitive activation. Yet, little attention has been devoted to gender-related alterations of MFV, including spectral analysis. In healthy subjects, fTCD was used to investigate a series of cerebral hemodynamic parameters in the middle cerebral arteries (MCA) during the Trail Making Tests (TMT), a means of selective attention and complex cognitive functioning. In females, there was a frequency peak at 0.375 Hz in both MCA, and we observed a dynamic shift in hemispheric dominance during that condition. Further, after the start phase, there was an MFV decline during complex functioning for the entire sample. These novel results suggest condition-specific features of cerebral hemodynamics in females, and it adds to the notion that gender is a fundamental confounder of brain physiology.

Reduced negative BOLD responses in the default-mode network and increased self-focus in depression.

OBJECTIVES: Functional imaging studies in major depressive disorder (MDD) indicate abnormal resting state neural activity and negative blood oxygenation level-dependent (BOLD) responses (NBRs) in regions of the default-mode network (DMN). METHODS: Since activity in DMN regions has been associated with self-relatedness, we investigated neural activity in these regions during self-related emotional judgement and passive picture viewing in 25 patients with MDD and 25 healthy controls in an event-related fMRI design. RESULTS: Behaviourally, MDD subjects showed significantly higher ratings of self-relatedness that also correlated with depression symptoms such as hopelessness. Neuroimaging results in MDD patients showed significantly lower negative BOLD responses (NBRs) in anterior medial cortical regions during judgement of self-relatedness while posterior medial regions showed increased NBRs. Unlike in healthy subjects, the anterior medial cortical NBRs were no longer parametrically modulated by the degree of self-relatedness in MDD patients. CONCLUSIONS: Our findings suggest that reduced NBRs in the anterior regions of the default-mode network may signify decoupling from self-relatedness in MDD patients with the consecutive abnormal increase of self-focus.

Self-regulation of cerebral blood flow by means of transcranial Doppler sonography biofeedback.

BACKGROUND: Transcranial Doppler sonography (TCD) allows the continuous non-invasive assessment of intracranial blood flow velocities with high temporal resolution. It may therefore prove suitable for biofeedback of cerebral perfusion. PURPOSE: The study explored whether healthy individuals can successfully be trained in self-regulation of cerebral blood flow using TCD biofeedback. METHODS: Twenty-two subjects received visual feedback of flow velocities in the middle cerebral arteries of both hemispheres. They were randomly assigned to two groups, one of which attempted to increase, the other to decrease the signal within eight training sessions. Heart rate and respiratory frequency were also monitored. RESULTS: Both groups achieved significant changes in flow velocities in the expected directions. Modulations in heart rate and respiratory frequency during biofeedback did not account for these effects. CONCLUSIONS: TCD biofeedback enables efficient self-regulation of cerebral blood flow. It is promising in applications such as the treatment of migraine and post-stroke rehabilitation.

Interactions between systemic hemodynamics and cerebral blood flow during attentional processing.

The study explored interactions between systemic hemodynamics and cerebral blood flow during attentional processing. Using transcranial Doppler sonography, blood flow velocities in the middle cerebral arteries (MCA) of both hemispheres were recorded while 50 subjects performed a cued reaction time task. Finger arterial pressure and heart rate were also continuously monitored. Doppler sonography revealed a right dominant blood flow response. The extent of the increase measured in second two of the interstimulus interval showed a clear positive association with reaction speed. Task-related changes in blood pressure and heart rate proved predictive of changes in MCA flow velocities in limited time windows of the response. Besides an association between cerebral blood flow and attentional performance, the results suggest a marked impact of systemic hemodynamics on the blood flow response. All observed interactions are highly dynamic in time.

Rapid cerebral hemodynamic modulation during set shifting: evidence of time-locked associations with cognitive control in females.

Set shifting provokes specific alterations of cerebral hemodynamics in basal cerebral arteries. However, no gender differences have been reported. In the following functional transcranial Doppler study, we introduced cerebral hemodynamic modulation to the aspects of set shifting during Wisconsin Card Sorting Test (WCST). Twenty-one subjects underwent the WCST during insonation of the middle cerebral arteries. We examined gender effects on task performance and cerebral hemodynamic modulation. Further, we investigated the linkage between performance and cerebral hemodynamic modulation. In females, maximum positive modulation was restricted to the behaviorally relevant time point of set shifting, and there were time-locked associations between mental slowing during set shifting and rapid cerebral hemodynamic modulation exclusively in females. This study provides evidence of gender-related cerebral hemodynamic modulation during set shifting, and we detected time-locked brain-behavior relationship during cognitive control in females.

Segregated neural representation of psychological and somatic-vegetative symptoms in severe major depression.

OBJECTIVE: The Beck Depression Inventory (BDI) is probably the most widely used depression scale. It has been suggested that it contains a two-factor structure measuring cognitive-affective (i.e. psychological) and somatic-vegetative depressive symptoms. In this study we aim to evaluate these factors by probing for their neural correlates. METHODS: Neural responses evoked by emotional perception, relative to an emotional judgment task, were measured using functional magnetic resonance imaging (fMRI) in 20 medication-free patients with severe MDD. Psychological and somatic-vegetative symptoms were evaluated with the BDI. RESULTS: Psychological symptoms correlated with signal changes in the dorsomedial and right ventrolateral prefrontal cortex, while somatic-vegetative symptoms correlated with signal changes in the pre-genual anterior cingulate cortex. CONCLUSIONS: These preliminary findings demonstrate segregated neural representation of psychological and somatic-vegetative symptoms of MDD in different cortical regions. Thus, our results indicate that the two-factor structure of the BDI is related to distinct neural correlates.

Increased self-focus in major depressive disorder is related to neural abnormalities in subcortical-cortical midline structures.

Patients with major depressive disorder (MDD) often show a tendency to strongly introspect and reflect upon their self, which has been described as increased self-focus. Although subcortical-cortical midline structures have been associated with reflection and introspection of oneself in healthy subjects, the neural correlates of the abnormally increased attribution of negative emotions to oneself, i.e. negative self-attribution, as hallmark of the increased self-focus in MDD remain unclear. The aim of the study was, therefore, to investigate the neural correlates during judgment of self-relatedness of positive and negative emotional stimuli thereby testing for emotional self-attribution. Using fMRI, we investigated 27 acute MDD patients and compared them with 25 healthy subjects employing a paradigm that focused on judgment of self-relatedness when compared with mere perception of the very same emotional stimuli. Behaviourally, patients with MDD showed significantly higher degrees of self-relatedness of specifically negative emotional stimuli when compared with healthy subjects. Neurally, patients with MDD showed significantly lower signal intensities in various subcortical and cortical midline regions like the dorsomedial prefrontal cortex (DMPFC), supragenual anterior cingulate cortex, precuneus, ventral striatum (VS), and the dorsomedial thalamus (DMT). Signal changes in the DMPFC correlated with depression severity and hopelessness whereas those in the VS and the DMT were related to judgment of self-relatedness of negative emotional stimuli. In conclusion, we present first evidence that the abnormally increased negative self-attribution as hallmark of the increased self-focus in MDD might be mediated by altered neural activity in subcortical-cortical midline structures.

Altered negative BOLD responses in the default-mode network during emotion processing in depressed subjects.

Studies using functional magnetic resonance imaging (fMRI) show predominant negative blood oxygenation level-dependent (BOLD) responses (NBRs) in regions of the default-mode network such as the pregenual anterior cingulate cortex, the ventromedial prefrontal cortex, and the posterior cingulate cortex. Patients with major depressive disorder (MDD) show emotional-cognitive disturbances, which have been associated with alterations within the default-mode network. However, it remains unclear whether these default-mode network alterations are related to abnormalities in NBRs. We therefore investigated neural activity in the default-mode network during different emotional tasks in patients with MDD in an event-related fMRI design. MDD patients showed significantly reduced NBRs in several regions of the default-mode network. Decreased NBRs in MDD patients correlated with depression severity and feelings of hopelessness. In sum, our findings demonstrate that default-mode network NBRs are reduced in MDD and modulate these patients' abnormally negative emotions.