Psychiatric Adverse Events of Acetylcholinesterase Inhibitors in Alzheimer's Disease and Parkinson's Dementia: Systematic Review and Meta-Analysis.

BACKGROUND: The acetylcholinesterase inhibitors (AChEIs) donepezil, galantamine, and rivastigmine are commonly used in the management of various forms of dementia. OBJECTIVES: While these drugs are known to induce classic cholinergic adverse events such as diarrhea, their potential to cause psychiatric adverse events has yet to be thoroughly examined. METHODS: We sought to determine the risk of psychiatric adverse events associated with the use of AChEIs through a systematic review and meta-analysis of double-blind randomized controlled trials involving patients with Alzheimer's dementia and Parkinson's dementia. RESULTS: A total of 48 trials encompassing 22,845 patients were included in our analysis. Anorexia was the most commonly reported psychiatric adverse event, followed by agitation, insomnia, and depression. Individuals exposed to AChEIs had a greater risk of experiencing appetite disorders, insomnia, or depression compared with those who received placebo (anorexia: odds ratio [OR] 2.93, 95% confidence interval [CI] 2.29-3.75; p < 0.00001; decreased appetite: OR 1.93, 95% CI 1.33-2.82; p = 0.0006; insomnia: OR 1.55, 95% CI 1.25-1.93; p < 0.0001; and depression: OR 1.59, 95% CI 1.23-2.06, p = 0.0004). Appetite disorders were also more frequent with high-dose versus low-dose therapy. A subgroup analysis revealed that the risk of insomnia was higher for donepezil than for galantamine. CONCLUSIONS: Our findings suggest that AChEI therapy may negatively impact psychological health, and careful monitoring of new psychiatric symptoms is warranted. Lowering the dose may resolve some psychiatric adverse events, as may switching to galantamine in the case of insomnia. CLINICAL TRIAL REGISTRATION: The study was pre-registered on PROSPERO (CRD42021258376).

Connected to the spirit of the frog: An Internet-based survey on Kambô, the secretion of the Amazonian Giant Maki Frog (Phyllomedusa bicolor): Motivations for use, settings and subjective experiences.

BACKGROUND/AIM: Kambô is a name for the secretion of the Giant Maki Frog (Phyllomedusa bicolor), which has been used by indigenous cultures from the Amazonas basin and has recently become popular in alternative healing circles in Western countries, with a certain overlap with psychedelic self-exploration. METHODS: We carried out an online-based survey in English (54.92%) and German investigating motivations for using Kambô, settings in which rituals take place, and subjective experiences during and after the application. RESULTS: Participants (n = 386, mean age: 38.08 years, (standard deviation = 9.95)) were well-educated individuals with an increased lifetime prevalence of the use of ayahuasca (67.88%). A plethora of motivations for using Kambô was reported, including general healing, detoxification and spiritual growth. Acute effects included severe physical reactions and mild psychoactive effects, most surprisingly, the feeling of being connected to the frog's spirit (41.97%), whereas predominantly positive persisting psychological effects were reported. Few participants reported long-lasting physical (2.85%) or mental (1.81%) health problems which they attributed to Kambô. Of the participants, 87.31% reported an increase in personal well-being or life satisfaction, and 64.26% considered Kambô to have been at least of 'very much' spiritual significance for their lives. CONCLUSIONS: The majority of users claimed beneficial effects including more health-orientated behaviors, whereas only very few participants complained about new health problems which they ascribed to Kambô. In retrospect, Kambô was given a high personal and spiritual significance by many participants. Additional research is needed to determine in how far reported effects are modulated by setting and subjective expectations.

The maternal brain in women with a history of early-life maltreatment: an imagination-based fMRI study of conflictual versus pleasant interactions with children.

BACKGROUND: Early-life maltreatment has severe consequences for the affected individual, and it has an impact on the next generation. To improve understanding of the intergenerational effects of abuse, we investigated the consequences of early-life maltreatment on maternal sensitivity and associated brain mechanisms during mother-child interactions. METHODS: In total, 47 mothers (22 with a history of physical and/or sexual childhood abuse and 25 without, all without current mental disorders) took part in a standardized real-life interaction with their 7- to 11-year-old child (not abused) and a subsequent functional imaging script-driven imagery task. RESULTS: Mothers with early-life maltreatment were less sensitive in real-life mother-child interactions, but while imagining conflictual interactions with their child, they showed increased activation in regions of the salience and emotion-processing network, such as the amygdala, insula and hippocampus. This activation pattern was in contrast to that of mothers without early-life maltreatment, who showed higher activations in those regions in response to pleasant mother-child interactions. Mothers with early-life maltreatment also showed reduced functional connectivity between regions of the salience and the mentalizing networks. LIMITATIONS: Region-of-interest analyses, which were performed in addition to whole-brain analyses, were exploratory in nature, because they were not further controlled for multiple comparisons. CONCLUSION: Results suggest that for mothers with early-life maltreatment, conflictual interactions with their child may be more salient and behaviourally relevant than pleasant interactions, and that their salience network is poorly modulated by the brain regions involved in mentalizing processes. This activation pattern offers new insights into the mechanisms behind the intergenerational effects of maltreatment and into options for reducing these effects.

Self-Compassion Mediates the Relationship Between Mindfulness and Borderline Personality Disorder Symptoms.

Individuals suffering from borderline personality disorder (BPD) experience difficulties with mindfulness. How mindfulness influences BPD symptoms, however, is still unknown. We hypothesized that the relationship between mindfulness and BPD symptoms would be mediated by self-compassion. In study 1, we recruited 29 individuals with BPD and 30 group-matched healthy controls. In study 2, we complemented our results with findings from a larger, nonclinical sample of 89 participants that were recruited during an open-house event at the local university. All participants completed questionnaires assessing self-compassion, mindfulness, BPD symptom severity, and emotion dysregulation. In both studies, self-compassion mediated the relationship between mindfulness and BPD symptom severity as well as between mindfulness and emotion dysregulation. Self-compassion seems to be one psychological process that could explain the relationship between mindfulness and BPD symptoms. One promising approach in therapy could be to target self-compassion more directly during mindfulness trainings and interventions.

Internal and external attention and the default mode network.

Focused attention meditations have been shown to improve psychological health and wellbeing and are nowadays an integral part of many psychotherapies. While research on the neural correlates of focused attention meditation is increasing, findings vary on whether meditations are associated with high or low activity in the default mode network (DMN). To clarify the relationship between focused attention meditation and the activity in DMN regions, it may be helpful to distinguish internal and external attention as well as different phases within one meditation: During focused attention meditation, the practitioner switches between mindful attention, mind-wandering and refocusing. Here, we employed a thought-probe paradigm to study the neural correlates of these different phases. Twenty healthy, meditation naïve participants were introduced to external (mindfulness of sound) and internal (mindfulness of breathing) attention meditation and then practiced the meditation at home for four consecutive days. They then performed the same focused attention meditations during fMRI scanning, in four runs alternating between internal and external attention. At pseudorandom intervals, participants were asked whether they had just been focused on the task (mindful attention) or had been distracted (mind-wandering). During mindful attention, brain regions typically associated with the DMN, such as the medial prefrontal cortex, posterior cingulate cortex and left temporoparietal junction showed significantly less neural activation compared to mind-wandering phases. Reduced activity of the DMN was found during both external and internal attention, with stronger deactivation in the posterior cingulate cortex during internal attention compared to external attention. Moreover, refocusing after mind-wandering was associated with activity in the left inferior frontal gyrus. Our results support the theory that mindful attention is associated with reduced DMN activity compared to mind-wandering, independent of the practitioner's attention focus (i.e., internal vs. external).

Neural correlates of alcohol-approach bias in alcohol addiction: the spirit is willing but the flesh is weak for spirits.

Behavioral studies have shown an alcohol-approach bias in alcohol-dependent patients: the automatic tendency to faster approach than avoid alcohol compared with neutral cues, which has been associated with craving and relapse. Although this is a well-studied psychological phenomenon, little is known about the brain processes underlying automatic action tendencies in addiction. We examined 20 alcohol-dependent patients and 17 healthy controls with functional magnetic resonance imaging (fMRI), while performing an implicit approach-avoidance task. Participants pushed and pulled pictorial cues of alcohol and soft-drink beverages, according to a content-irrelevant feature of the cue (landscape/portrait). The critical fMRI contrast regarding the alcohol-approach bias was defined as (approach alcohol>avoid alcohol)>(approach soft drink>avoid soft drink). This was reversed for the avoid-alcohol contrast: (avoid alcohol>approach alcohol)>(avoid soft drink>approach soft drink). In comparison with healthy controls, alcohol-dependent patients had stronger behavioral approach tendencies for alcohol cues than for soft-drink cues. In the approach, alcohol fMRI contrast patients showed larger blood-oxygen-level-dependent responses in the nucleus accumbens and medial prefrontal cortex, regions involved in reward and motivational processing. In alcohol-dependent patients, alcohol-craving scores were positively correlated with activity in the amygdala for the approach-alcohol contrast. The dorsolateral prefrontal cortex was not activated in the avoid-alcohol contrast in patients vs controls. Our data suggest that brain regions that have a key role in reward and motivation are associated with the automatic alcohol-approach bias in alcohol-dependent patients.

Shape conveyed by visual-to-auditory sensory substitution activates the lateral occipital complex.

The lateral-occipital tactile-visual area (LOtv) is activated when objects are recognized by vision or touch. We report here that the LOtv is also activated in sighted and blind humans who recognize objects by extracting shape information from visual-to-auditory sensory substitution soundscapes. Recognizing objects by their typical sounds or learning to associate specific soundscapes with specific objects do not activate this region. This suggests that LOtv is driven by the presence of shape information.

Pedophilia is linked to reduced activation in hypothalamus and lateral prefrontal cortex during visual erotic stimulation.

BACKGROUND: Although pedophilia is of high public concern, little is known about underlying neural mechanisms. Although pedophilic patients are sexually attracted to prepubescent children, they show no sexual interest toward adults. This study aimed to investigate the neural correlates of deficits of sexual and emotional arousal in pedophiles. METHODS: Thirteen pedophilic patients and 14 healthy control subjects were tested for differential neural activity during visual stimulation with emotional and erotic pictures with functional magnetic resonance imaging. RESULTS: Regions showing differential activations during the erotic condition comprised the hypothalamus, the periaqueductal gray, and dorsolateral prefrontal cortex, the latter correlating with a clinical measure. Alterations of emotional processing concerned the amygdala-hippocampus and dorsomedial prefrontal cortex. CONCLUSIONS: Hypothesized regions relevant for processing of erotic stimuli in healthy individuals showed reduced activations during visual erotic stimulation in pedophilic patients. This suggests an impaired recruitment of key structures that might contribute to an altered sexual interest of these patients toward adults.

Go-no-go task performance improvement after anodal transcranial DC stimulation of the left dorsolateral prefrontal cortex in major depression.

BACKGROUND: We recently showed that repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex (DLPFC) can affect the performance in an affective go-no-go (AGN) task. We aimed to extend this previous investigation testing whether one session of anodal transcranial direct current stimulation (tDCS) of the left DLPFC, as compared with anodal occipital and sham tDCS, affects this AGN task performance. METHODS: Twenty-six patients with major depression were randomized to receive anodal tDCS of the left DLPFC, occipital cortex or sham tDCS (the cathode electrode was placed over the frontopolar area for the three conditions). An AGN task was performed immediately before and after treatment. Performance changes (pre and post-treatment) were compared across groups of treatment and correlated with Hamilton Depression Rating Scale (HDRS) score changes. RESULTS: The results show that anodal stimulation of the left DLPFC was the only condition that induced a significant improvement in task performance as shown by the increase in the number of correct responses. In addition, this effect was specific for figures with positive emotional content. This performance enhancement was not correlated with mood changes after 10 days of tDCS treatment. LIMITATIONS: Although the effects of tDCS are less focal than rTMS, it can induce a longer and stronger modulation of cortical excitability. CONCLUSIONS: Our findings suggest that left DLPFC activity is associated with positive emotional processing, confirming and extending results of previous studies that associated right DLPFC and orbito-frontal cortex activity with emotional processing. Furthermore the effects of tDCS on mood and cognition seem to be independent in major depression. These lines of evidence together shed light on the neural circuitry involved with emotional processing in major depression.

Anodal transcranial direct current stimulation of prefrontal cortex enhances working memory.

Previous studies have claimed that weak transcranial direct current stimulation (tDCS) induces persisting excitability changes in the human motor cortex that can be more pronounced than cortical modulation induced by transcranial magnetic stimulation, but there are no studies that have evaluated the effects of tDCS on working memory. Our aim was to determine whether anodal transcranial direct current stimulation, which enhances brain cortical excitability and activity, would modify performance in a sequential-letter working memory task when administered to the dorsolateral prefrontal cortex (DLPFC). Fifteen subjects underwent a three-back working memory task based on letters. This task was performed during sham and anodal stimulation applied over the left DLPFC. Moreover seven of these subjects performed the same task, but with inverse polarity (cathodal stimulation of the left DLPFC) and anodal stimulation of the primary motor cortex (M1). Our results indicate that only anodal stimulation of the left prefrontal cortex, but not cathodal stimulation of left DLPFC or anodal stimulation of M1, increases the accuracy of the task performance when compared to sham stimulation of the same area. This accuracy enhancement during active stimulation cannot be accounted for by slowed responses, as response times were not changed by stimulation. Our results indicate that left prefrontal anodal stimulation leads to an enhancement of working memory performance. Furthermore, this effect depends on the stimulation polarity and is specific to the site of stimulation. This result may be helpful to develop future interventions aiming at clinical benefits.