Bipolar disorder type I and II show distinct relationships between cortical thickness and executive function.

OBJECTIVE: Frontal cortical abnormalities and executive function impairment co-occur in bipolar disorder. Recent studies have shown that bipolar subtypes differ in the degree of structural and functional impairments. The relationships between cognitive performance and cortical integrity have not been clarified and might differ across patients with bipolar disorder type I, II, and healthy subjects. METHOD: Using a vertex-wise whole-brain analysis, we investigated how cortical integrity, as measured by cortical thickness, correlates with executive performance in patients with bipolar disorder type I, II, and controls (N = 160). RESULTS: We found focal associations between executive function and cortical thickness in the medial prefrontal cortex in bipolar II patients and controls, but not in bipolar I disorder. In bipolar II patients, we observed additional correlations in lateral prefrontal and occipital regions. CONCLUSIONS: Our findings suggest that bipolar disorder patients show altered structure-function relationships, and importantly that those relationships may differ between bipolar subtypes. The findings are line with studies suggesting subtype-specific neurobiological and cognitive profiles. This study contributes to a better understanding of brain structure-function relationships in bipolar disorder and gives important insights into the neuropathophysiology of diagnostic subtypes.

Subcortical volumetric abnormalities in bipolar disorder.

Considerable uncertainty exists about the defining brain changes associated with bipolar disorder (BD). Understanding and quantifying the sources of uncertainty can help generate novel clinical hypotheses about etiology and assist in the development of biomarkers for indexing disease progression and prognosis. Here we were interested in quantifying case-control differences in intracranial volume (ICV) and each of eight subcortical brain measures: nucleus accumbens, amygdala, caudate, hippocampus, globus pallidus, putamen, thalamus, lateral ventricles. In a large study of 1710 BD patients and 2594 healthy controls, we found consistent volumetric reductions in BD patients for mean hippocampus (Cohen's d=-0.232; P=3.50 × 10-7) and thalamus (d=-0.148; P=4.27 × 10-3) and enlarged lateral ventricles (d=-0.260; P=3.93 × 10-5) in patients. No significant effect of age at illness onset was detected. Stratifying patients based on clinical subtype (BD type I or type II) revealed that BDI patients had significantly larger lateral ventricles and smaller hippocampus and amygdala than controls. However, when comparing BDI and BDII patients directly, we did not detect any significant differences in brain volume. This likely represents similar etiology between BD subtype classifications. Exploratory analyses revealed significantly larger thalamic volumes in patients taking lithium compared with patients not taking lithium. We detected no significant differences between BDII patients and controls in the largest such comparison to date. Findings in this study should be interpreted with caution and with careful consideration of the limitations inherent to meta-analyzed neuroimaging comparisons.

Why sickness hurts: A central mechanism for pain induced by peripheral inflammation.

Low-grade systemic inflammation has been implicated in chronic pain, as well as in comorbid diseases like depression and fatigue. We have previously shown that women's pain perception and regulation is more affected by systemic inflammation than that of men. Here we investigated the neural substrates underlying these effects using an fMRI paradigm previously employed in a clinical population. Fifty-one participants (29 women) were injected with 0.6ng/kg lipopolysaccharide (LPS) or saline to induce a peripheral inflammatory response. The subjects were then tested with a pressure pain fMRI paradigm designed to capture descending pain inhibitory activity 2h after injection, and blood was sampled for cytokine analysis. The subjects injected with LPS became more pain sensitive compared to the placebo group, and the heightened pain sensitivity was paralleled by decreased activity in the ventrolateral prefrontal cortex and the rostral anterior cingulate cortex (rACC) compared to placebo; areas involved in descending pain regulation. The LPS group also had higher activity in the anterior insular cortex, an area underpinning affective and interoceptive pain processing. Women displayed overall less pain-evoked rACC activity compared to men, which may have rendered women less resilient to immune provocation, possibly explaining sex differences in LPS-induced pain sensitivity. Our findings elucidate the pain-related brain circuits affected by experimental peripheral inflammation, strengthening the theoretical link between systemic inflammation and weakened pain regulation in chronic pain disorders. The results further suggest a possible mechanism underlying the female predominance in many chronic pain disorders.

Modality and sex differences in pain sensitivity during human endotoxemia.

Systemic inflammation can induce pain hypersensitivity in animal and human experimental models, and has been proposed to be central in clinical pain conditions. Women are overrepresented in many chronic pain conditions, but experimental studies on sex differences in pain regulation during systemic inflammation are still scarce. In two randomized and double blind placebo controlled experiments, we used low doses of lipopolysaccharide (LPS) as an experimental model of systemic inflammation. The first study employed 0.8ng/kg LPS in a within-subject design of 8 individuals (1 woman), and the second study 0.6ng/kg LPS in a between-subject design of 52 participants (29 women). We investigated the effect on (a) pressure, heat, and cold pain thresholds, (b) suprathreshold noxious heat and cold sensitivity, and (c) conditioned pain modulation (CPM), and differences between men and women. LPS induced significantly lower pressure pain thresholds as compared to placebo (mean change with the 0.8ng/kg dose being -64±30kPa P=.04; with the 0.6ng/kg dose -58±55kPa, P<.01, compared to before injection), whereas heat and cold pain thresholds remained unaffected (P's>.70). Suprathreshold noxious pain was not affected by LPS in men (P's⩾.15). However, LPS made women rated suprathreshold noxious heat stimuli as more painful (P=.01), and showed a tendency to rate noxious cold pain as more painful (P=.06) as compared to placebo. Furthermore, LPS impaired conditioned pain modulation, a measure of endogenous pain inhibition, but this effect was also restricted to women (P<.01, for men P=.27). Pain sensitivity correlated positively with plasma IL-6 and IL-8 levels. The results show that inflammation more strongly affects deep pain, rather than cutaneous pain, and suggest that women's pain perception and modulation is more sensitive to immune activation than men's.

Cognitive flexibility is associated with sickness resilience.

Psychological constructs related to health outcomes and well-being, such as metacognitive beliefs, have been linked to executive functions in general, and cognitive flexibility more specifically. However, such effects have previously only been discussed on a theoretical level and behavioral flexibility has most often been measured through self-report, only approximating information processing capacities. Objectively measured executive functions may be a more potent predictor of health outcomes. We set out to test whether cognitive flexibility capacity was associated with sick leave in a medium sized company. We included 111 subjects of widely different occupations and assessed their executive functions using Delis-Kaplan Executive Function System test battery (D-KEFS). To assess cognitive flexibility capacity, we included Design Fluency (DF) and Verbal Fluency (VF) and computed these into an index of cognitive flexibility (DFVF). Detailed information on sick leave for the last 5 years was gathered from the company. Our results showed that there was a significant negative correlation between DFVF and sick leave [rs(109) = -0.23, p = 0.015] in the full group as well as in the group that had at least 1 day of sick leave [rs(72) = -0.25, p = 0.03]. The results withstood adjustment for sex, age, occupation, and several core executive functions as well as autistic and ADHD-traits. The results remained for separate analyses using DF or VF. Our main findings were conceptually replicated in a group of bipolar disorder patients. This study shows that objectively measured capacity of cognitive flexibility is associated with key health outcomes such as sick leave.

COVID-19 conspiracy ideation is associated with the delusion proneness trait and resistance to update of beliefs.

The rapid spread of conspiracy ideas associated with the recent COVID-19 pandemic represents a major threat to the ongoing and coming vaccination programs. Yet, the cognitive factors underlying the pandemic-related conspiracy beliefs are not well described. We hypothesized that such cognitive style is driven by delusion proneness, a trait phenotype associated with formation of delusion-like beliefs that exists on a continuum in the normal population. To probe this hypothesis, we developed a COVID-19 conspiracy questionnaire (CCQ) and assessed 577 subjects online. Their responses clustered into three factors that included Conspiracy, Distrust and Fear/Action as identified using principal component analysis. We then showed that CCQ (in particular the Conspiracy and Distrust factors) related both to general delusion proneness assessed with Peter's Delusion Inventory (PDI) as well as resistance to belief update using a Bias Against Disconfirmatory Evidence (BADE) task. Further, linear regression and pathway analyses suggested a specific contribution of BADE to CCQ not directly explained by PDI. Importantly, the main results remained significant when using a truncated version of the PDI where questions on paranoia were removed (in order to avoid circular evidence), and when adjusting for ADHD- and autistic traits (that are known to be substantially related to delusion proneness). Altogether, our results strongly suggest that pandemic-related conspiracy ideation is associated with delusion proneness trait phenotype.

Manic episodes are associated with grey matter volume reduction - a voxel-based morphometry brain analysis.

OBJECTIVE: To investigate whether the lifetime number of affective episodes or illness duration is associated with changes in local grey matter volume, in patients with bipolar I disorder without comorbid conditions. METHOD: Magnetic resonance imaging scans of 55 patients with bipolar I disorder were analysed using VBM. RESULTS: Smaller grey matter volume in the inferior frontal gyri of the dorsolateral prefrontal cortices (DLPFC) correlated significantly to the lifetime number of manic episodes. No association between local grey matter volume and the lifetime number of depression episodes or illness duration was found. CONCLUSION: We found strong evidence for a linear correlation between a decrease in DLPFC volume and the lifetime number of manic episodes in patients with bipolar I disorder. Interestingly, DLPFC is known to be important for executive functions and the findings in this study might hence be linked to the executive cognitive deficits associated with bipolar disorder.

Heart rate variability (HRV) in adolescent females with anxiety disorders and major depressive disorder.

AIM: The aim of this study was to investigate heart rate variability (HRV) in a clinical sample of female adolescents with anxiety disorders (AD) and/or major depressive disorder (MDD) compared with healthy controls and to assess the effect of selective serotonin reuptake inhibitors (SSRI) on HRV. METHODS: Heart rate variability was measured in adolescent female psychiatric patients with AD and/or MDD (n = 69), mean age 16.8 years (range: 14.5-18.4), from 13 out-patient clinics and in healthy controls (n = 65), mean age 16.5 years (range: 15.9-17.7). HRV was registered in the sitting position during 4 min with no interventions. RESULTS: Logarithmically transformed high frequency HRV (HF), low frequency HRV (LF) and standard deviation of inter beat intervals (SDNN) were lower in the clinical sample compared with the controls (Cohen's d for HF = 0.57, LF = 0.55, SDNN = 0.60). This was not explained by body mass index, blood pressure or physical activity. Medication with SSRI explained 15.5% of the total variance of HF, 3.0% of LF and 6.5% of SDNN. CONCLUSIONS: Adolescent female psychiatric patients with AD and/or MDD show reduced HRV compared with healthy controls. Medication with SSRI explained a part of this difference.

[Generics of antiepileptic drugs]. / Génériques des médicaments antiépileptiques.

Generic substitution of antiepileptic drugs (EAD) have limited use because epilepsy is a chronic disease, seizure recurrence has an important impact of the quality of life and the potential risk of accidents. EADs have a narrow therapeutic window, non negligible side effects and complex interactions. Bioavailability of generic EADs, tested in healthy men during a limited period of time must be within the 90% IC, in which means that serum levels can range from 80% to 125% of the original drug. A slight drop in serum level could increase the risk of seizure recurrence, as indicated by several publications. Although no formal studies regarding cost effectiveness and the rate of seizure recurrence is available yet, the prevailing consensus recommends not to replace an original antiepileptic drug by a generic, due to the harmful risk of seizure recurrence.

[Mental disorders and epilepsies]. / Troubles psychiques et épilepsies.

Mental disorders in patients having difficulties to treat their epilepsy are without a doubt more frequent than those presented by patients with controlled epilepsies or within a general population. These problems are especially affective disorders; clinical presentations of these troubles are often particular and difficult to classify through the current admitted classification guidelines. We speak generally about an interictal dysphoric disorder. The relationship between observed troubles in seizures is in some cases very particular: postictal depressions and psychosis are very peculiar disorders, self limited, difficult to detect and to treat. Some considerations are made about certain topics related to severe epilepsies: suicide, pseudo seizures and therapeutic attitude.

Level of play and coach-rated game intelligence are related to performance on design fluency in elite soccer players.

Executive brain functions are innate mechanisms for regulating behavior. While the impact of suboptimal executive functions has been characterized in patients, their contribution to individual success has not been elucidated. We set out to understand how executive functions relate to successful human behavior by examining their relation to game intelligence in sport - the ability to read a game and quickly adapt the behavior. In elite soccer players (n = 51), those playing in national teams (national team players) significantly outperformed those only playing at premier league level (premier league players) in Design Fluency (DF), a complex visuo-spatial executive function test that includes measures of creativity and cognitive flexibility. Their result showed a moderate correlation with coach rated game intelligence, remained also when correcting for low level cognitive capacity and was most evident when considering cognitive flexibility. DF capacity also correlated with number of assists made during the season but not with number of made goals during the same period, linking the fast planning of several steps in DF to fast planning of several steps in the soccer game. Altogether, our data suggests that DF capacity relates to success in soccer both on a subjective and on an objective level.

Perfusion abnormalities in hemimegalencephaly.

INTRODUCTION: Cerebrovascular changes are rarely discussed in patients with hemimegalencephaly. These alterations have previously been associated with epileptical activity. CASE: We report the case of a 36-week gestation neonate presenting with total right hemimegalencephaly, as demonstrated by a magnetic resonance imaging (MRI) performed in the first days of life. Perfusion-weighted imaging displayed a clear hypervascularization of the right hemisphere. Diffusion-tensor imaging showed an arrangement of white matter fibers concentrically around the ventricle on the right hemisphere. AngioMRI showed an obvious asymmetry in the size of the middle cerebral arteries, with the right middle cerebral artery being prominent. The baby was free of clinical seizures during his first week of life. An electroencephalogram at that time displayed an asymmetric background activity, but no electrical seizures. CONCLUSION: Perfusion anomalies in hemimegalencephaly may not necessarily be related to epileptical activity, but may be related to vessel alterations.

Altered deactivation in individuals with genetic risk for Alzheimer's disease.

Regions that show task-induced deactivations may be part of a default-mode network related to processes that are more engaged during passive than active task conditions. Alteration of task-induced deactivations with age and dementia is indicated by atypical engagement of default-mode network regions. Genetic studies show a relation between the apolipoprotein E4 (APOE4) allele and the common form of Alzheimer's disease (AD), and altered functional brain activation has been observed in non-demented APOE4 carriers compared to non-carriers. Here we investigate the hypothesis of altered default-mode network brain responses in individuals with genetic risk for AD. Functional MRI was used to assess task-induced deactivation in 60 subjects of which 30 carried at least one copy of the APOE4 allele, and 30 non-carriers. Subjects were scanned while performing a semantic categorization task shown to promote episodic memory encoding. The results show patterns of deactivation consistent with the default-mode network. We also found reduced deactivation in non-demented APOE4 carriers compared to non-carriers, suggesting alterations in the default-mode network in the absence of dementia. These results implicate possibilities for investigating altered properties of task-induced deactivations in individuals with genetic risk for AD, and may prove useful for pre-clinical identification of individuals susceptible to memory problems and AD.

The role of long-term physical exercise on performance and brain activation during the Stroop colour word task in fibromyalgia patients.

The Stroop colour word test (SCWT) has been widely used to assess changes in cognitive performance such as processing speed, selective attention and the degree of automaticity. Moreover, the SCWT has proven to be a valuable tool to assess neuronal plasticity that is coupled to improvement in performance in clinical populations. In a previous study, we showed impaired cognitive processing during SCWT along with reduced task-related activations in patients with fibromyalgia. In this study, we used SCWT and functional magnetic resonance imagingFMRI to investigate the effects of a 15-week physical exercise intervention on cognitive performance, task-related cortical activation and distraction-induced analgesia (DIA) in patients with fibromyalgia and healthy controls. The exercise intervention yielded reduced fibromyalgia symptoms, improved cognitive processing and increased task-related activation of amygdala, but no effect on DIA. Our results suggest beneficial effects of physical exercise on cognitive functioning in FM.

Effects of subtle cognitive manipulations on placebo analgesia - An implicit priming study.

BACKGROUND: Expectancy is widely accepted as a key contributor to placebo effects. However, it is not known whether non-conscious expectancies achieved through semantic priming may contribute to placebo analgesia. In this study, we investigated if an implicit priming procedure, where participants were unaware of the intended priming influence, affected placebo analgesia. METHODS: In a double-blind experiment, healthy participants (n = 36) were randomized to different implicit priming types; one aimed at increasing positive expectations and one neutral control condition. First, pain calibration (thermal) and a credibility demonstration of the placebo analgesic device were performed. In a second step, an independent experimenter administered the priming task; Scrambled Sentence Test. Then, pain sensitivity was assessed while telling participants that the analgesic device was either turned on (placebo) or turned off (baseline). Pain responses were recorded on a 0-100 Numeric Response Scale. RESULTS: Overall, there was a significant placebo effect (p < 0.001), however, the priming conditions (positive/neutral) did not lead to differences in placebo outcome. Prior experience of pain relief (during initial pain testing) correlated significantly with placebo analgesia (p < 0.001) and explained 34% of placebo variance. Trait neuroticism correlated positively with placebo analgesia (p < 0.05) and explained 21% of placebo variance. CONCLUSIONS: Priming is one of many ways to influence behaviour, and non-conscious activation of positive expectations could theoretically affect placebo analgesia. Yet, we found no SST priming effect on placebo analgesia. Instead, our data point to the significance of prior experience of pain relief, trait neuroticism and social interaction with the treating clinician. SIGNIFICANCE: Our findings challenge the role of semantic priming as a behavioural modifier that may shape expectations of pain relief, and affect placebo analgesia.

Effect of nitrous oxide on local cerebral glucose utilization in rats.

The influence of 70-80% N2O on local local cerebral glucose utilization (CMRg1) in the rat brain was studied with the [14C]deoxyglucose method in minimally restrained, spontaneously breathing animals 75 min following discontinuation of halothane anaesthesia. Nitrous oxide was found to have only small effects on local CMRg1 in the majority of the 25 structures analyzed. When corrections were made for a small difference in body temperature between nitrous oxide--breathing animals and those breathing air nitrous oxide was found to significantly increase local CMRg1 in some subcortical structures by 15-25% (red nucleus, thalamus, geniculate bodies, and superior colliculus), and to decrease local CMRg1 in nucleus accumbens and sensorimotor cortex by comparable amounts. Thus, although nitrous oxide does not alter overall glucose utilization in the brain, it differentially affects CMRg1 in some brain structures.

Metabolic alterations underlying the development of hypermetabolic necrosis in the substantia nigra in status epilepticus.

The substantia nigra pars reticulata (SNPR) has previously been shown to undergo tissue necrosis following status epilepticus induced by flurothyl in the rat. Even if the rat is ventilated, the SNPR develops necrosis if the epileptic period lasts more than 30 min. Rat brains were frozen in situ after 20 and 60 min of seizure activity and after 60 min of seizure activity followed by 60 min recovery. Labile energy metabolites were then analyzed in the SNPR and in the periaqueductal grey matter (PAG, control region). In the PAG, the metabolite changes during status epilepticus were similar to those reported for cerebral cortex and hippocampus. Measurements showed an unchanged ATP content and energy charge (97% and 98% of control, respectively) and an accumulation of lactate to 9.2 +/- 0.6 mumol/g in the 60-min group. In the PAG, all metabolites measured had returned to control values after 60 min of recovery. In the SNPR, the perturbation of the energy metabolites was much more pronounced during status epilepticus. The concentration of ATP decreased to 75 +/- 3%, the energy charge to 91% +/- 12% and the adenylate pool to 86.7 +/- 5.7% of control. Lactate accumulated to concentrations of 16.1 +/- 1.8 mumol/g and 24.9 +/- 2.3 mumol/g in the 20-min and 60-min groups, respectively. The concentration of lactate was still increased above control after 60 min recovery, whereas the concentration of ATP and the energy charge were lower than control. The findings demonstrate that sustained and intense neuronal activation can cause metabolic disturbance and thereby lead to necrosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Regional differences in vascular autoregulation in the rat brain in severe insulin-induced hypoglycemia.

The present experiments were undertaken to determine if loss of vascular autoregulation during severe hypoglycemia shows regional differences that could help to explain the localization of hypoglycemic cell damage. Artificially ventilated rats (70% N2O) were subjected to a 30-min insulin-induced hypoglycemic coma (with cessation of EEG activity), with mean arterial blood pressure being maintained at 140, 120, 100, and 80 mm Hg. After 30 min of hypoglycemia, local cerebral blood flow (CBF) in 25 brain structures was measured autoradiographically with a [14C]iodoantipyrine technique. Since local CBF values did not differ between the 120 and the 100 mm Hg groups, the animals of these groups were pooled (110 mm Hg group). The results showed that at a blood pressure of 140 mm Hg, CBF was increased in 22 of 25 structures analyzed, the maximal values approximating 300% of control. At 110 mm Hg, cerebral cortical structures had CBF values that were either decreased, normal, or slightly increased; however, many subcortical structures (and cerebellum) showed markedly increased flow rates. Although a lowering of blood pressure to 80 mm Hg usually further reduced flow rates, some of these latter structures also had well-maintained CBF values at that pressure. Thus, there were large interstructural variations of local CBF at any of the pressures examined. Analysis of the pressure-flow relationship showed loss of autoregulation in some structures, whereas others had remarkably well-preserved CBF values at low pressures. The results indicate that during severe hypoglycemia, even relatively moderate arterial hypotension may add a circulatory insult to the primary one, and they strongly suggest that any such insult affects some brain structures more than others.

Effect of propranolol on local cerebral blood flow under normocapnic and hypercapnic conditions.

The effect of propranolol (2.5 mg kg-1, i.v.) on local cerebral blood flow (CBF) in normocapnia was studied in rats maintained artificially ventilated on 70% N2O and 30% O2. The method used was autoradiography with [14C]iodoantipyrine. Although a single dose of propranolol, given 30 min prior to CBF measurements, somewhat reduced mean CBF values in all of the 22 structures analysed, none of the changes were significant. The results confirm previous ones, in which overall CBF was measured, in showing that beta-adrenergic mechanisms have little effect on normal cerebrovascular tone. Following a single dose of propranolol, results obtained in hypercapnia were equally negative; neither did CBF fall significantly when propranolol was given by constant infusion during 15 min. Furthermore, local CBF did not differ between animals infused with dl-propranolol and d-propranolol. It is concluded that in the rat, propranolol has but small effects on the CBF response to hypercapnia, if any. The results reveal that local CO2 responsiveness, calculated as delta CBF/delta PCO2, varies with normocapnic flow rates.