Daniel Schuepbach

Imbalance between left and right dorsolateral prefrontal cortex in major depression is linked to negative emotional judgment: an fMRI study in severe major depressive disorder

BACKGROUND Although recent neuroimaging and therapeutic transcranial magnetic cortex stimulation (TMS) studies suggest imbalance between left and right dorsolateral prefrontal cortex (DLPFC) in major depressive disorder (MDD) the fundamental neuropsychological characterization of left DLPFC hypoactivity and right DLPFC hyperactivity in MDD remains poorly understood. METHODS We used event-related functional magnetic resonance imaging (fMRI) to investigate neural activity in left and right DLPFC related to unattended (unexpected) and attended (expected) judgment of emotions. Participating in the study were 20 medication-free patients with MDD and 30 healthy subjects. RESULTS The MDD patients showed hypoactivity in the left DLPFC during both unattended and attended emotional judgment and hyperactivity in the right DLPFC during attended emotional judgment. In contrast to healthy subjects, left DLPFC activity during emotional judgment was not parametrically modulated by negative emotional valence and was inversely modulated by positive emotional valence in MDD patients. Hyperactivity in the right DLPFC correlated with depression severity. CONCLUSIONS Results demonstrate that left DLPFC hypoactivity is associated with negative emotional judgment rather than with emotional perception or attention while right DLPFC hyperactivity is linked to attentional modulation. Left-right DLPFC imbalance is characterized in neuropsychological regard, which bridges the gap from resting metabolism and therapeutic repetitive transcranial magnetic stimulation effects to functional neuroanatomy of altered emotional-cognitive interaction in MDD.

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. Hum Brain Mapp, 2009.

Pretreatment and longitudinal studies of neuropsychological deficits in antipsychotic-naïve patients with schizophrenia

The early course of neuropsychological dysfunction in schizophrenia and the impact of treatment on these deficits need to be better specified. A sample of 45 patients with schizophrenia underwent five neuropsychological evaluations from prior to treatment with antipsychotic treatment through a 2-year follow-up period. A comparison sample of 33 matched healthy individuals underwent neuropsychological evaluations at similar time points. At baseline, a generalized deficit across cognitive domains was evident for the schizophrenia sample. After 6 weeks of treatment, patients showed modest improvements in visual memory and visual perception, but a decline in verbal memory. Verbal memory performance returned to baseline levels by the 6-month follow-up while deficits in other neuropsychological domains persisted throughout the 2-year period. Relatively static and generalized neuropsychological dysfunction, evident from illness onset, is consistent with neurodevelopmental rather than neurodegenerative models of schizophrenia.

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

Abstract 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.

Negative symptom resolution and improvements in specific cognitive deficits after acute treatment in first-episode schizophrenia

Patients with first-episode schizophrenia show significant cognitive impairments even at this early phase of their illness. Antipsychotic medication improves clinical symptomatology, but the effectiveness of this treatment on neuropsychological deficits remains unclear. We investigated clinical symptom and neuropsychological performance change in 34 unmedicated first-episode psychotic patients (17 males, 17 females) from the time prior to treatment until 33.6+/-11.3 days after treatment initiation at which time patients demonstrated meaningful recovery from psychosis. Twenty-four matched healthy subjects were also studied. Performance in most neuropsychological functions (language skills, attention, nonverbal learning and reasoning, motor speed) remained stable for the group as a whole. However, reduction in negative symptoms was significantly correlated with performance increases in verbal fluency and attention. Higher negative symptom recovery was associated with improvement of cognitive performance to levels approaching those of healthy subjects, whereas low or no negative symptom improvement was associated with stable or decreased cognitive performance. Reduction in positive symptoms was not associated with change in cognitive abilities. These findings suggest a linkage between early, treatment-induced improvements in negative symptoms and reductions in distinct cognitive deficits.

Time-locked association between rapid cerebral blood flow modulation and attentional performance

OBJECTIVE The study investigated relationships between rapid cerebral hemodynamic modulation and attentional performance. Based on former results on complex cognitive functioning, a specific association between the first seconds of the hemodynamic response and performance was hypothesized. METHODS Using transcranial Doppler sonography, blood flow velocities in the middle cerebral arteries of both hemispheres were recorded in 48 healthy subjects. The applied task comprised motor reactions on a visual stimulus which was preceded by an acoustic warning signal (interstimulus interval 5s). Task-induced hemodynamic changes were assessed second-by-second, and related to reaction time using analysis of variance and linear regression. RESULTS A right dominant blood flow response was observed. Flow velocity increase in the middle fraction of the interstimulus interval, i.e. seconds 2 and 3 after the cuing signal, significantly correlated with reaction time. This was not the case for the very early and late components of the response. CONCLUSIONS The results suggest a time-locked association between cerebral blood flow increase and attentional performance. This is in accordance with neurophysiological studies that revealed the closest relationship between brain perfusion and cortical activity during a similar time window. SIGNIFICANCE The study supports the assumption of a specific, relatively early time interval in which relationships between cerebral blood flow and behavior become apparent.

Rapid cerebral hemodynamic modulation during mental planning and movement execution: evidence of time-locked relationship with complex behavior.

OBJECTIVE Although there is evidence of specific associations between neuronal activity and early cerebral blood flow (CBF), little is known on a logical furtherance of this linkage, namely the association between early measures of cerebral hemodynamics and complex behavior. The present study examined the linkage between hemodynamic modulation in basal cerebral arteries and performance in a non-routine planning task by means of functional transcranial Doppler sonography (fTCD). METHODS The Stockings of Cambridge (SOC) was employed as planning paradigm. The middle and anterior cerebral arteries (MCA/ACA) were bilaterally insonated. Statistical methods comprised uni- and multivariate analyses of variance and multiple linear regression analyses. RESULTS Taking advantage of the excellent temporal resolution of fTCD, early cerebral hemodynamic modulation of the left MCA markedly predicted task accuracy. Pronounced early blood flow increase during planning and early decrease during movement execution were associated with better performance. No such blood flow modulations were observed in worse performers. CONCLUSIONS Early cerebral hemodynamic modulation in the left MCA proved to be a valuable neurophysiological marker that showed a great overlap with task accuracy during non-routine planning. SIGNIFICANCE These results support the notion that a high temporal resolution in functional monitoring is a favorable strategy to disentangle relevant neurophysiological correlates of higher cognitive functioning.

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 (&bgr; = .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. Abbreviations FMS = fibromyalgia syndrome fMRI = functional magnetic resonance imaging fTCD = functional transcranial Doppler sonography ACAs = anterior cerebral arteries MCAs = middle cerebral arteries SCID = Structured Clinical Interview for Axis I Disorders MPQ = McGill Pain Questionnaire BDI = Beck Depression Inventory STAI = State-Trait Anxiety Inventory VAS = visual analog scale VIF = variance inflation factor BOLD = blood oxygen level dependent EEG = electroencephalography

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.

Specific alterations of cerebral hemodynamics during a planning task: a transcranial Doppler sonography study

Planning plays an important role in daily activities, and several experimental paradigms have been investigated with brain imaging methods showing activity in putative brain regions such as dorsolateral prefrontal cortex and other frontal and non-frontal regions. The Stockings of Cambridge (SOC), a related procedure to the Tower of London task, was introduced to 21 healthy subjects while they underwent bilateral transcranial Doppler sonography (TCD) of the middle (MCA) and anterior (ACA) cerebral arteries. Different levels of difficulty were applied during continuous registration of peak mean cerebral blood flow velocity (CBFV). A specific test procedure allowed separating the actual planning from the execution phase. There was also a similar control task, which did not involve planning. CBFV differed among the planning, execution, and control conditions (MCA: P < 0.01; ACA: P < 0.001), but did not show a significant difference between the MCA and ACA (P > 0.1). Easy tasks yielded a more rapid increase of CBFV in the MCA compared to difficult problems during planning (P < 0.05). In conclusion, our findings of specific CBFV patterns support the idea of different cognitive challenges for planning and control and between easy and difficult conditions.