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BioRxiv : the Preprint Server For... May 2024Emerging research in non-human animals implicates cerebellar projections to the ventral tegmental area (VTA) in appetitive behaviors, but these circuits have not been...
Emerging research in non-human animals implicates cerebellar projections to the ventral tegmental area (VTA) in appetitive behaviors, but these circuits have not been characterized in humans. Here, we mapped cerebello-VTA white-matter connectivity in humans using probabilistic tractography on diffusion imaging data from the Human Connectome Project. We uncovered the topographical organization of these connections by separately tracking from parcels of cerebellar lobule VI, crus I/II, vermis, paravermis, and cerebrocerebellum. Results revealed that connections from the cerebellum to the VTA predominantly originate in the right hemisphere, interposed nucleus, and paravermal cortex, and terminate mostly ipsilaterally. Paravermal crus I sends the most connections to the VTA compared to other lobules. We discovered a medial-to-lateral gradient of connectivity, such that the medial cerebellum has the highest connectivity with the VTA. Individual differences in microstructure were associated with measures of negative affect and social functioning. By splitting the tracts into quarters, we found that the socio-affective effects were driven by the third quarter of the tract, corresponding to the point at which the fibers leave the deep nuclei. Taken together, we produced detailed maps of cerebello-VTA structural connectivity for the first time in humans and established their relevance for trait differences in socio-affective regulation.
PubMed: 38798382
DOI: 10.1101/2023.09.29.560239 -
American Journal of Men's Health 2024Being a man has been recognized as a salient risk factor for suicide. Adopting uncompromised masculine perceptions (i.e., conforming to the masculine gender role norms)...
Being a man has been recognized as a salient risk factor for suicide. Adopting uncompromised masculine perceptions (i.e., conforming to the masculine gender role norms) may restrict emotional expressiveness in men, which, in turn, may contribute to depression and somatization symptoms. We examined the moderating role of psychological flexibility and alexithymia in the relationship of masculinity with depression and somatization symptoms. A sample of 119 men completed measures of masculinity, alexithymia (difficulty identifying and delivering subjective feelings), psychological flexibility, depression, and somatization symptoms in a cross-sectional design study. Psychological flexibility levels moderated the relationship between masculinity and depression symptoms: Masculinity contributed as positively associated with depression symptoms when psychological flexibility was low, but no such association was found at moderate or high levels of psychological flexibility. As a cognitive factor promoting adaptive emotional regulation, psychological flexibility might reduce depression symptoms among inflexible masculine men. Clinical implications relate to diagnosing at-risk subgroups and their treatment.
Topics: Humans; Male; Masculinity; Israel; Adult; Cross-Sectional Studies; Depression; Young Adult; Middle Aged; Adaptation, Psychological; Surveys and Questionnaires; Affective Symptoms
PubMed: 38794957
DOI: 10.1177/15579883241253820 -
Journal of Clinical Medicine May 2024Alexithymia is characterized by a deficit in identifying and communicating feelings. Emerging evidence suggests that alexithymia is highly prevalent in migraine, in a...
Alexithymia is characterized by a deficit in identifying and communicating feelings. Emerging evidence suggests that alexithymia is highly prevalent in migraine, in a complex interplay with psychiatric comorbidity. Pericranial/cervical muscle tenderness is a remarkable clinical feature in a large proportion of migraine patients. This pilot study aimed at investigating the relationship between alexithymia and pericranial/cervical muscle tenderness in female migraineurs. A total of 42 female patients fulfilling the diagnostic criteria for migraine were enrolled into this pilot, observational, cross-sectional study after informed consent was obtained. Each patient underwent a psychological assessment to identify any alexithymia by means of TAS-20, anxiety/mood comorbidity (by means of STAI-Y1 STAI-Y2, BDI-II), and migraine-related disability (by means of HIT-6), and a physical cranial/cervical musculoskeletal examination. Palpation of pericranial and cervical muscles was carried out in the standardized manner. A Cumulative Muscle Tenderness (CUM) score (0-6) was calculated for each patient. A multivariate analysis was performed to investigate any association amongst the TAS-20 score, the CUM score, and the following covariates: BDI-II, STAI-Y1, STAI-Y2, and HIT-6 scores, age, disease duration, monthly migraine days, and average head pain intensity in the previous three months. Overall, 35.6% of the sample had alexithymia. The multivariate analysis detected a linear and independent relationship between the TAS-20 and CUM scores, with a statistically significant ( = 0.017) association. This pilot study suggests that alexithymia plays a role in increasing pericranial/cervical muscle tenderness in migraine, independently from psychiatric comorbidity. A novel therapeutical approach, targeting alexithymia, may well reduce muscular tenderness in female migraineurs.
PubMed: 38792315
DOI: 10.3390/jcm13102772 -
Molecular Autism May 2024Social affective and communication symptoms are central to autism spectrum disorder (ASD), yet their severity differs across toddlers: Some toddlers with ASD display...
BACKGROUND
Social affective and communication symptoms are central to autism spectrum disorder (ASD), yet their severity differs across toddlers: Some toddlers with ASD display improving abilities across early ages and develop good social and language skills, while others with "profound" autism have persistently low social, language and cognitive skills and require lifelong care. The biological origins of these opposite ASD social severity subtypes and developmental trajectories are not known.
METHODS
Because ASD involves early brain overgrowth and excess neurons, we measured size and growth in 4910 embryonic-stage brain cortical organoids (BCOs) from a total of 10 toddlers with ASD and 6 controls (averaging 196 individual BCOs measured/subject). In a 2021 batch, we measured BCOs from 10 ASD and 5 controls. In a 2022 batch, we tested replicability of BCO size and growth effects by generating and measuring an independent batch of BCOs from 6 ASD and 4 control subjects. BCO size was analyzed within the context of our large, one-of-a-kind social symptom, social attention, social brain and social and language psychometric normative datasets ranging from N = 266 to N = 1902 toddlers. BCO growth rates were examined by measuring size changes between 1- and 2-months of organoid development. Neurogenesis markers at 2-months were examined at the cellular level. At the molecular level, we measured activity and expression of Ndel1; Ndel1 is a prime target for cell cycle-activated kinases; known to regulate cell cycle, proliferation, neurogenesis, and growth; and known to be involved in neuropsychiatric conditions.
RESULTS
At the BCO level, analyses showed BCO size was significantly enlarged by 39% and 41% in ASD in the 2021 and 2022 batches. The larger the embryonic BCO size, the more severe the ASD social symptoms. Correlations between BCO size and social symptoms were r = 0.719 in the 2021 batch and r = 0. 873 in the replication 2022 batch. ASD BCOs grew at an accelerated rate nearly 3 times faster than controls. At the cell level, the two largest ASD BCOs had accelerated neurogenesis. At the molecular level, Ndel1 activity was highly correlated with the growth rate and size of BCOs. Two BCO subtypes were found in ASD toddlers: Those in one subtype had very enlarged BCO size with accelerated rate of growth and neurogenesis; a profound autism clinical phenotype displaying severe social symptoms, reduced social attention, reduced cognitive, very low language and social IQ; and substantially altered growth in specific cortical social, language and sensory regions. Those in a second subtype had milder BCO enlargement and milder social, attention, cognitive, language and cortical differences.
LIMITATIONS
Larger samples of ASD toddler-derived BCO and clinical phenotypes may reveal additional ASD embryonic subtypes.
CONCLUSIONS
By embryogenesis, the biological bases of two subtypes of ASD social and brain development-profound autism and mild autism-are already present and measurable and involve dysregulated cell proliferation and accelerated neurogenesis and growth. The larger the embryonic BCO size in ASD, the more severe the toddler's social symptoms and the more reduced the social attention, language ability, and IQ, and the more atypical the growth of social and language brain regions.
Topics: Humans; Autism Spectrum Disorder; Organoids; Male; Female; Child, Preschool; Cerebral Cortex; Social Behavior; Organ Size; Infant; Severity of Illness Index; Brain
PubMed: 38790065
DOI: 10.1186/s13229-024-00602-8 -
Neuropharmacology Sep 2024Neuromodulation such as deep brain stimulation (DBS) is advancing as a clinical intervention in several neurological and neuropsychiatric disorders, including... (Review)
Review
Concerning neuromodulation as treatment of neurological and neuropsychiatric disorder: Insights gained from selective targeting of the subthalamic nucleus, para-subthalamic nucleus and zona incerta in rodents.
Neuromodulation such as deep brain stimulation (DBS) is advancing as a clinical intervention in several neurological and neuropsychiatric disorders, including Parkinson's disease, dystonia, tremor, and obsessive-compulsive disorder (OCD) for which DBS is already applied to alleviate severely afflicted individuals of symptoms. Tourette syndrome and drug addiction are two additional disorders for which DBS is in trial or proposed as treatment. However, some major remaining obstacles prevent this intervention from reaching its full therapeutic potential. Side-effects have been reported, and not all DBS-treated individuals are relieved of their symptoms. One major target area for DBS electrodes is the subthalamic nucleus (STN) which plays important roles in motor, affective and associative functions, with impact on for example movement, motivation, impulsivity, compulsivity, as well as both reward and aversion. The multifunctionality of the STN is complex. Decoding the anatomical-functional organization of the STN could enhance strategic targeting in human patients. The STN is located in close proximity to zona incerta (ZI) and the para-subthalamic nucleus (pSTN). Together, the STN, pSTN and ZI form a highly heterogeneous and clinically important brain area. Rodent-based experimental studies, including opto- and chemogenetics as well as viral-genetic tract tracings, provide unique insight into complex neuronal circuitries and their impact on behavior with high spatial and temporal precision. This research field has advanced tremendously over the past few years. Here, we provide an inclusive review of current literature in the pre-clinical research fields centered around STN, pSTN and ZI in laboratory mice and rats; the three highly heterogeneous and enigmatic structures brought together in the context of relevance for treatment strategies. Specific emphasis is placed on methods of manipulation and behavioral impact.
Topics: Subthalamic Nucleus; Animals; Deep Brain Stimulation; Zona Incerta; Mental Disorders; Humans; Nervous System Diseases; Rodentia
PubMed: 38789078
DOI: 10.1016/j.neuropharm.2024.110003 -
Behavioral Sciences (Basel, Switzerland) May 2024Alcohol and cannabis use are each associated with impairments in emotion recognition accuracy, which may promote interpersonal problems. It is unclear if emotion...
Alcohol and cannabis use are each associated with impairments in emotion recognition accuracy, which may promote interpersonal problems. It is unclear if emotion recognition or self-reported emotion processing differs between young adult alcohol and cannabis co-users (ACCs) and healthy controls (HCs). This study examined whether ACCs and HCs differed in their emotion recognition across two different behavioral tasks with static or dynamic faces and determined if there were differences in self-reported socio-emotional processing and alexithymia. 22 ACCs (mean age = 21.27 ± 1.75) and 25 HCs (mean age = 21.48 ± 2.68), matched on age, sex, and IQ, completed the Metrisquare Emotion Recognition Task and CANTAB Emotion Recognition Task. The ACCs and HCs were compared on task accuracy and self-reported measures, including the Social Emotional Questionnaire (SEQ) and the Perth Alexithymia Questionnaire (PAQ). No significant main effects of the Group variable or the Emotion-Group interaction variable were present for either task. The ACCs had lower SEQ ( = 0.014) and higher PAQ ( = 0.024) scores relative to the HCs, indicating greater difficulties in socio-emotional processing and identifying one's own emotions, respectively. Understanding the behavioral correlates of the self-reported difficulties in emotion processing reported by ACCs is needed to develop interventions to reduce these symptoms and promote healthy socio-emotional functioning in this population.
PubMed: 38785898
DOI: 10.3390/bs14050407 -
Alzheimer's & Dementia (New York, N. Y.) 2024Individuals with Alzheimer's disease (AD) commonly experience neuropsychiatric symptoms of psychosis (AD+P) and/or affective disturbance (depression, anxiety, and/or...
INTRODUCTION
Individuals with Alzheimer's disease (AD) commonly experience neuropsychiatric symptoms of psychosis (AD+P) and/or affective disturbance (depression, anxiety, and/or irritability, AD+A). This study's goal was to identify the genetic architecture of AD+P and AD+A, as well as their genetically correlated phenotypes.
METHODS
Genome-wide association meta-analysis of 9988 AD participants from six source studies with participants characterized for AD+P AD+A, and a joint phenotype (AD+A+P).
RESULTS
AD+P and AD+A were genetically correlated. However, AD+P and AD+A diverged in their genetic correlations with psychiatric phenotypes in individuals without AD. AD+P was negatively genetically correlated with bipolar disorder and positively with depressive symptoms. AD+A was positively correlated with anxiety disorder and more strongly correlated than AD+P with depressive symptoms. AD+P and AD+A+P had significant estimated heritability, whereas AD+A did not. Examination of the loci most strongly associated with the three phenotypes revealed overlapping and unique associations.
DISCUSSION
AD+P, AD+A, and AD+A+P have both shared and divergent genetic associations pointing to the importance of incorporating genetic insights into future treatment development.
HIGHLIGHTS
It has long been known that psychotic and affective symptoms are often comorbid in individuals diagnosed with Alzheimer's disease. Here we examined for the first time the genetic architecture underlying this clinical observation, determining that psychotic and affective phenotypes in Alzheimer's disease are genetically correlated.Nevertheless, psychotic and affective phenotypes in Alzheimer's disease diverged in their genetic correlations with psychiatric phenotypes assessed in individuals without Alzheimer's disease. Psychosis in Alzheimer's disease was negatively genetically correlated with bipolar disorder and positively with depressive symptoms, whereas the affective phenotypes in Alzheimer's disease were positively correlated with anxiety disorder and more strongly correlated than psychosis with depressive symptoms.Psychosis in Alzheimer's disease, and the joint psychotic and affective phenotype, had significant estimated heritability, whereas the affective in AD did not.Examination of the loci most strongly associated with the psychotic, affective, or joint phenotypes revealed overlapping and unique associations.
PubMed: 38784964
DOI: 10.1002/trc2.12472 -
Trials May 2024Relatives of patients with bipolar disorder (BD) often experience emotional burden with stress and depressive symptoms that again increase the likelihood of...
Study protocol: group-based psychoeducation for relatives of patients with bipolar disorder-a large scale real-world randomized controlled parallel group trial, the R-bipolar RCT.
BACKGROUND
Relatives of patients with bipolar disorder (BD) often experience emotional burden with stress and depressive symptoms that again increase the likelihood of destabilization and relapses in the patient. The effects of group-based psychoeducation have not been investigated in large-scale real-world settings. We are currently conducting a large-scale real-world randomized controlled parallel group trial (RCT) to test whether group-based psychoeducation for 200 relatives to patients with BD improves mood instability and other critical outcomes in relatives and the corresponding patients with BD.
METHODS
The trial is designed as a two-arm, parallel-group randomized trial with a balanced randomization 1:1 to either group-based psychoeducation or a waiting list for approximately 4 months and subsequent group-based psychoeducation. The primary outcome measure is mood instability calculated based on daily smartphone-based mood self-assessments. Other relevant outcomes are measured, including patients' reported outcomes, assessing self-assessed burden, self-efficacy, and knowledge about BD.
DISCUSSION
This protocol describes our currently ongoing randomized controlled trial (RCT) that aims at investigating group-based psychoeducation as an intervention for relatives of individuals diagnosed with bipolar disorder (BD). The study is the first large-scale real-world RCT to focus on a relatively short intervention of psychoeducation (6 sessions of 2 h each) in a large group of relatives (approximately 30 participants per group). With this focus, we wish to test an intervention that is feasible to implement in real-life psychiatric settings with limited budgets and time. It is also the first study to use mood instability in relatives as the primary outcome measure and to investigate whether mood instability and other affective symptoms in patients and relatives covary. It could be considered as limitations, that the trial is not blinded and does not include long-term follow-up.
TRIAL REGISTRATION
ClinicalTrials.gov NCT06176001. Registered on 2023-12-19. The study is approved by the data agency (P-2021-809). The project was allowed to be initiated without permission from the Scientific Ethical Committees for the Capital Region, because it according to section 1, paragraph 4 of the Committee Act was not defined as a health scientific intervention study (case number 21063013).
Topics: Humans; Bipolar Disorder; Randomized Controlled Trials as Topic; Family; Affect; Psychotherapy, Group; Treatment Outcome; Patient Education as Topic; Self Efficacy; Adult; Patient Reported Outcome Measures; Health Knowledge, Attitudes, Practice; Caregivers; Female
PubMed: 38783322
DOI: 10.1186/s13063-024-08172-z -
Journal of Affective Disorders Aug 2024Freud proposed that excessive self-blame-related motivations such as self-punishing tendencies play a key role in depression. Most of the supporting evidence, however,...
BACKGROUND
Freud proposed that excessive self-blame-related motivations such as self-punishing tendencies play a key role in depression. Most of the supporting evidence, however, is based on cross-sectional studies and questionnaire measures.
METHODS
In this pre-registered (NCT04593537) study, we used a novel Virtual Reality (VR) task to determine whether maladaptive self-blame-related action tendencies prospectively identify a subgroup of depression with poor prognosis when treated as usual over four months in primary care. Ninety-eight patients with depression (Patient Health Questionnaire-9 ≥ 15), screening negatively for bipolar and alcohol/substance use disorders, completed the VR-task at baseline (n = 93 completed follow-up).
RESULTS
Our pre-registered statistical/machine learning model prospectively predicted a cross-validated 19 % of variance in depressive symptoms. Contrary to our specific predictions, and in accordance with Freud's observations, feeling like punishing oneself emerged as prognostically relevant rather than feeling like hiding or creating a distance from oneself. Using a principal components analysis of all pre-registered continuous measures, a factor most strongly loading on feeling like punishing oneself for other people's wrongdoings (β = 0.23, p = 0.01), a baseline symptom factor (β = 0.30, p = 0.006) and Maudsley Staging Method treatment-resistance scores (β = 0.28, p = 0.009) at baseline predicted higher depressive symptoms after four months.
LIMITATIONS
Patients were not assessed with a diagnostic interview.
CONCLUSIONS
Independently and apart from known clinical variables, feeling like punishing oneself emerged as a distinctly relevant prognostic factor and should therefore be assessed and tackled in personalised care pathways for difficult-to-treat depression.
Topics: Humans; Female; Male; Adult; Prognosis; Middle Aged; Virtual Reality; Depression; Interpersonal Relations; Prospective Studies; Motivation; Guilt; Depressive Disorder; Machine Learning
PubMed: 38777276
DOI: 10.1016/j.jad.2024.05.098 -
PloS One 2024Misophonia is a condition characterized by negative affect, intolerance, and functional impairment in response to particular repetitive sounds usually made by others...
Misophonia is a condition characterized by negative affect, intolerance, and functional impairment in response to particular repetitive sounds usually made by others (e.g., chewing, sniffing, pen tapping) and associated stimuli. To date, researchers have largely studied misophonia using self-report measures. As the field is quickly expanding, assessment approaches need to advance to include more objective measures capable of differentiating those with and without misophonia. Although several studies have used sounds as experimental stimuli, few have used standardized stimuli sets with demonstrated reliability or validity. To conduct rigorous research in an effort to better understand misophonia, it is important to have an easily accessible, standardized set of acoustic stimuli for use across studies. Accordingly, in the present study, the International Affective Digitized Sounds (IADS-2), developed by Bradley and Lang (Bradley MM et al., 2007), were used to determine whether participants with misophonia responded to certain standardized sounds differently than a control group. Participants were 377 adults (132 participants with misophonia and 245 controls) recruited from an online platform to complete several questionnaires and respond to four probes (arousal, valence, similarity to personally-relevant aversive sounds, and sound avoidance) in response to normed pleasant, unpleasant, and neutral IADS-2 sounds. Findings indicated that compared to controls, participants with high misophonia symptoms rated pleasant and neutral sounds as significantly more (a) arousing and similar to trigger sounds in their everyday life, (b) unpleasant and (c) likely to be avoided in everyday life. For future scientific and clinical innovation, we include a ranked list of IADS-2 stimuli differentiating responses in those with and without misophonia, which we call the IADS-M.
Topics: Humans; Female; Male; Adult; Sound; Middle Aged; Acoustic Stimulation; Surveys and Questionnaires; Young Adult; Affect
PubMed: 38776286
DOI: 10.1371/journal.pone.0301105