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Background: We recently reported that Mediterranean (MED) and green-MED diets significantly attenuated age-related brain atrophy by ∼50% within 18 mo., Objective: The objective of this study was to explore the contribution of specific diet-induced parameters to brain-volume deviation from chronologic age., Methods: A post hoc analysis of the 18-mo DIRECT PLUS trial, where participants were randomly assigned to the following groups: 1) healthy dietary guidelines, 2) MED diet, or 3) green-MED diet, high in polyphenols, and low in red meat. Both MED groups consumed 28 g walnuts/d (+440 mg/d polyphenols). The green-MED group further consumed green tea (3-4 cups/d) and Mankai green shake (Wolffia globosa aquatic plant) (+800 mg/d polyphenols). We collected blood samples through the intervention and followed brain structure volumes by magnetic resonance imaging (MRI). We used hippocampal occupancy (HOC) score (hippocampal and inferior lateral-ventricle volumes ratio) as a neurodegeneration marker and brain-age proxy. We applied multivariate linear regression models., Results: Of 284 participants [88% male; age = 51.1 y; body mass index = 31.2 kg/m 2 ; hemoglobin A1c (HbA1c) = 5.48%; APOE-ε4 genotype = 15.7%], 224 completed the trial with eligible whole-brain MRIs. Individuals with higher HOC deviations (i.e., younger brain age) presented lower body weight [r = -0.204; 95% confidence interval (CI): -0.298, -0.101], waist circumference (r = -0.207; 95% CI: -0.310, -0.103), diastolic (r = -0.186; 95% CI: -0.304, -0.072), systolic blood pressure (r = -0.189; 95% CI: -0.308, -0.061), insulin (r = -0.099; 95% CI: -0.194, -0.004), and HbA1c (r = -0.164; 95% CI: -0.337, -0.006) levels. After 18 mo, greater changes in HOC deviations (i.e., brain-age decline attenuation) were independently associated with improved HbA1c (β = -0.254; 95% CI: -0.392, -0.117), HOMA-IR (β = -0.200; 95% CI: -0.346, -0.055), fasting glucose (β = -0.155; 95% CI: -0.293, -0.016), and c-reactive protein (β = -0.153; 95% CI: -0.296, -0.010). Improvement in diabetes status was associated with greater HOC deviation changes than either no change in diabetes status (0.010; 95% CI: 0.002, 0.019) or with an unfavorable change (0.012; 95% CI: 0.002, 0.023). A decline in HbA1c was further associated with greater deviation changes in the thalamus, caudate nucleus, and cerebellum (P < 0.05). Greater consumption of Mankai and green tea (green-MED diet components) were associated with greater HOC deviation changes beyond weight loss., Conclusions: Glycemic control contributes to the neuroprotective effects of the MED and green-MED diets on brain age. Polyphenols-rich diet components as Mankai and green tea may contribute to a more youthful brain age. This trial was registered at clinicaltrials.gov at clinicaltrials.gov as NCT03020186., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The effect of diet on age-related brain atrophy is largely unproven., Objectives: We aimed to explore the effect of a Mediterranean diet (MED) higher in polyphenols and lower in red/processed meat (Green-MED diet) on age-related brain atrophy., Methods: This 18-mo clinical trial longitudinally measured brain structure volumes by MRI using hippocampal occupancy score (HOC) and lateral ventricle volume (LVV) expansion score as neurodegeneration markers. Abdominally obese/dyslipidemic participants were randomly assigned to follow 1) healthy dietary guidelines (HDG), 2) MED, or 3) Green-MED diet. All subjects received free gym memberships and physical activity guidance. Both MED groups consumed 28 g walnuts/d (+440 mg/d polyphenols). The Green-MED group consumed green tea (3-4 cups/d) and Mankai (Wolffia-globosa strain, 100 g frozen cubes/d) green shake (+800 mg/d polyphenols)., Results: Among 284 participants (88% men; mean age: 51 y; BMI: 31.2 kg/m2; APOE-ε4 genotype = 15.7%), 224 (79%) completed the trial with eligible whole-brain MRIs. The pallidum (-4.2%), third ventricle (+3.9%), and LVV (+2.2%) disclosed the largest volume changes. Compared with younger participants, atrophy was accelerated among those ≥50 y old (HOC change: -1.0% ± 1.4% compared with -0.06% ± 1.1%; 95% CI: 0.6%, 1.3%; P < 0.001; LVV change: 3.2% ± 4.5% compared with 1.3% ± 4.1%; 95% CI: -3.1%, -0.8%; P = 0.001). In subjects ≥ 50 y old, HOC decline and LVV expansion were attenuated in both MED groups, with the best outcomes among Green-MED diet participants, as compared with HDG (HOC: -0.8% ± 1.6% compared with -1.3% ± 1.4%; 95% CI: -1.5%, -0.02%; P = 0.042; LVV: 2.3% ± 4.7% compared with 4.3% ± 4.5%; 95% CI: 0.3%, 5.2%; P = 0.021). Similar patterns were observed among younger subjects. Improved insulin sensitivity over the trial was the parameter most strongly associated with brain atrophy attenuation (P < 0.05). Greater Mankai, green tea, and walnut intake and less red and processed meat were significantly and independently associated with reduced HOC decline (P < 0.05). Elevated urinary concentrations of the polyphenols urolithin-A (r = 0.24; P = 0.013) and tyrosol (r = 0.26; P = 0.007) were significantly associated with lower HOC decline., Conclusions: A Green-MED (high-polyphenol) diet, rich in Mankai, green tea, and walnuts and low in red/processed meat, is potentially neuroprotective for age-related brain atrophy.This trial was registered at clinicaltrials.gov as NCT03020186., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Background: Evidence points toward shared characteristics between female survivors of sexual abuse and women with dyspareunia. This study explored, for the first time, similarities and differences between women who were exposed to sexual abuse to those with dyspareunia, in order to examine whether insecure attachment styles and high somatization level are associated with trauma among women with dyspareunia., Methods: Attachment styles were explored using the Experience in Close Relationships Scale to reflect participants' levels of anxiety and avoidance. Somatization was assessed using the Brief Symptom Inventory focusing on the frequency of painful and non-painful bodily complaints. Trauma was categorized into three levels: sexual trauma, nonsexual trauma, and no trauma., Results: Sexually abused (SA) women (n = 21) compared to women with dyspareunia (dys) (n = 44) exhibited insecure attachment styles, as expressed by high levels of avoidance (SA 4.10 ± 0.99 vs. dys 3.08 ± 1.04, t (61)  = 2.66, p = .01) and anxiety (SA 4.29 ± 1.22 vs. dys 3.49 ± 1.04, t (61)  = 3.61, p = .001), and higher somatization (21.00 ± 8.25 vs. 13.07 ± 7.57, t (59)  = 3.63, p = .001). Attachment and somatization level did not differ significantly between women with dyspareunia without trauma to those with nonsexual trauma., Conclusions: Our findings emphasized the unique role of sexual trauma as a contributing factor to the augmentation of perceived bodily symptoms and to insecure attachment style. This illuminates the importance of disclosing previous sexual abuse history among women with dyspareunia.

Objective: Suicidal ideation and behavior currently have no quick-acting pharmacological treatments that are suitable for independent outpatient use. Suicidality is linked to mental pain, which is modulated by the separation distress system through endogenous opioids. The authors tested the efficacy and safety of very low dosages of sublingual buprenorphine as a time-limited treatment for severe suicidal ideation., Method: This was a multisite randomized double-blind placebo-controlled trial of ultra-low-dose sublingual buprenorphine as an adjunctive treatment. Severely suicidal patients without substance abuse were randomly assigned to receive either buprenorphine or placebo (in a 2:1 ratio), in addition to their ongoing individual treatments. The primary outcome measure was change in suicidal ideation, as assessed by the Beck Suicide Ideation Scale at the end of each of 4 weeks of treatment., Results: Patients who received ultra-low-dose buprenorphine (initial dosage, 0.1 mg once or twice daily; mean final dosage=0.44 mg/day; N=40) had a greater reduction in Beck Suicide Ideation Scale scores than patients who received placebo (N=22), both after 2 weeks (mean difference -4.3, 95% CI=-8.5, -0.2) and after 4 weeks (mean difference=-7.1, 95% CI=-12.0, -2.3). Concurrent use of antidepressants and a diagnosis of borderline personality disorder did not affect the response to buprenorphine. No withdrawal symptoms were reported after treatment discontinuation at the end of the trial., Conclusions: The time-limited, short-term use of very low dosages of sublingual buprenorphine was associated with decreased suicidal ideation in severely suicidal patients without substance abuse. Further research is needed to establish the efficacy, safety, dosing, and appropriate patient populations for this experimental treatment.

Recent advances in the cognitive, affective and social neurosciences have enabled these fields to study aspects of the mind that are central to psychoanalysis. These developments raise a number of possibilities for psychoanalysis. Can it engage the neurosciences in a productive and mutually enriching dialogue without compromising its own integrity and unique perspective? While many analysts welcome interdisciplinary exchanges with the neurosciences, termed neuropsychoanalysis, some have voiced concerns about their potentially deleterious effects on psychoanalytic theory and practice. In this paper we outline the development and aims of neuropsychoanalysis, and consider its reception in psychoanalysis and in the neurosciences. We then discuss some of the concerns raised within psychoanalysis, with particular emphasis on the epistemological foundations of neuropsychoanalysis. While this paper does not attempt to fully address the clinical applications of neuropsychoanalysis, we offer and discuss a brief case illustration in order to demonstrate that neuroscientific research findings can be used to enrich our models of the mind in ways that, in turn, may influence how analysts work with their patients. We will conclude that neuropsychoanalysis is grounded in the history of psychoanalysis, that it is part of the psychoanalytic worldview, and that it is necessary, albeit not sufficient, for the future viability of psychoanalysis., (Copyright © 2015 Institute of Psychoanalysis.)

Mammalian brains contain at least 7 primal emotional systems--Seeking, Rage, Fear, Lust, Care, Panic and Play (capitalization reflects a proposed primary-process terminology, to minimize semantic confusions and mereological fallacies). These systems help organisms feel affectively balanced (e.g. euthymic) and unbalanced (e.g. depressive, irritable, manic), providing novel insights for understanding human psychopathologies. Three systems are especially important for understanding depression: The separation distress (Panic) system mediates the psychic pain of separation distress (i.e. excessive sadness and grief), which can be counteracted by minimizing Panic arousals (as with low-dose opioids). Depressive dysphoria also arises from reduced brain reward-seeking and related play urges (namely diminished enthusiasm (Seeking) and joyful exuberance (Play) which promote sustained amotivational states). We describe how an understanding of these fundamental emotional circuits can promote the development of novel antidepressive therapeutics--(i) low-dose buprenorphine to counteract depression and suicidal ideation emanating from too much psychic pain (Panic overarousal), (ii) direct stimulation of the Seeking system to counteract amotivational dysphoria, and (iii) the discovery and initial clinical testing of social-joy-promoting molecules derived from the analysis of the Play system., (© 2014 S. Karger AG, Basel.)

Objectives: This study assessed the interactive effect of two risk factors: "Juvenile stress" and sex in the long-term consequences of "Juvenile stress" in male and female rats., Methods: Rats were exposed to "Juvenile stress" and to additional stress in adulthood. Measurements of anxiety and depressive-like behaviours were assessed in relation to each stress exposure and "Sex-specific" sets of criteria in order to characterize individual profiles of altered behaviours., Results: While both male and female rats were affected by exposure to "Juvenile stress", sex difference were evident in saccharine preference, coping with the stressful challenge of the two-way shuttle avoidance task, and on "Adult stress" induced changes in saccharine preference. "Profiling" altered behaviours revealed sex differences also in the prevalence of rats exhibiting different categories of "Affected" behaviours, indicating that female rats are more susceptible to the long-term effects of "Juvenile stress" and to the immediate effects of "Adulthood stress". Additionally, the prevalence of "Affected" animals among "Juvenile+ Adulthood stress" was similar, yet the profile of altered behaviours was significantly different., Conclusions: The "Behavioural Profiling" approach presented here is of importance to understanding gender differences in the aetiology of predisposition to stress-related disorders, and of gender symptomatology differences in stress-related disorders.

Objectives: Women with a history of sexual abuse (SA) commonly report greater pain symptoms. It is still unclear whether enhanced pain susceptibility is the result of altered pain processing and response. Therefore, this pilot study aimed to explore pain sensitivity to experimentally induced pain and associated psychology in women with a history of severe SA., Methods: Twenty-one survivors of severe, long-lasting SA and 21 control women underwent experimentally induced heat pain and completed psychological questionnaires. Pain measures included heat pain thresholds, pain intensity ratings, and pain tolerance in response to contact heat, painful stimulation delivered to the volar forearm. Questionnaires included somatization (Brief Symptom Inventory), personality traits including harm avoidance, novelty seeking, and reward dependence (Cloninger tridimensional personality questionnaire), and levels of dissociation (Dissociative Experiences Scale)., Results: SA women had elevated heat pain thresholds (45.7±2.2°C vs. 43.9±3.1°C; P=0.042) and higher pain intensity ratings (on a 0 to 100 scale: 80.0±26.6 vs. 51.2±27.7; P=0.001). In addition, they had lower tolerability to painful tonic stimulation, greater somatization, and larger harm avoidance scores. Regression analyses showed that higher pain intensity ratings in SA women associated with greater tendency for harm avoidance but not with levels of dissociation., Discussion: Women with a history of severe SA seem to have a paradoxical pattern of experimental pain response, characterized by both higher pain thresholds and increased pain intensity ratings. This pattern is associated with the personality trait of harm avoidance. Models that might account for these findings are discussed.

In this study, the authors explored the relations among painful experience during sexual intercourse, attachment style, and somatization. The authors assessed these variables by self-report of dyspareunia (painful vaginal intercourse) and by completion of the Experience in Close Relationships Scale and the short version of the Brief Symptom Inventory. The sample included 110 women, 45 of whom reported painful intercourse and were defined as the dyspareunia group, and the remaining 65 were defined as the control group. The dyspareunia group showed greater incidence, compared with the control group, of insecure attachment styles defined by higher scores of anxiety and/or avoidance as well as higher somatization levels. Regression analyses revealed that increased level of somatization and higher level of avoidance predicted higher probability for dyspareunia. The authors' findings suggest that women with higher frequency of physical complaints in various body areas and insecure attachment style are more susceptible to report pain during intercourse.

Objective: Traumatic amnesia has been amply documented in the psychoanalytic literature but inconsistently in the research literature., Method: Six trauma were followed prospectively. Survivors were interviewed 7, 30, and 120 days following the traumatic event. Each interview documented in detail their recollections of the day of their trauma., Results: In four subjects who did not develop posttraumatic stress disorder (PTSD), we found brief, stable, and persistent memory gaps, which coincided with the moment of greatest emotional intensity. In two subjects who developed PTSD, we found, in addition to the previous form of amnesia, longer, progressive, and unstable memory gaps., Discussion: Neurobiological research offers two explanatory mechanisms for the observations: A failure of acquisition of episodic memories may account for the stable deficits seen in all subjects. This could coincide with stress-induced malfunction of the hippocampal declarative memory system. A failure of spontaneous recall may account for the more extended traumatic amnesia that was observed in PTSD patients. This resembles the psychoanalytic description of repression., Conclusion: These preliminary findings suggest that brief, irreversible memory gaps are common in trauma survivors, whereas longer, progressive, and potentially reversible amnesia occurs among survivors who develop PTSD.

An important recent insight in a number of neurobiological systems is that during learning, individual dually regulated proteins with associative properties function as critical sites of stimulus convergence. During conditioning in Aplysia, the Ca2+ /calmodulin-sensitive adenylyl cyclase (AC) in mechanosensory neurons serves as a molecular site of interaction between Ca2+ and serotonin [5-hydroxytryptamine (5-HT)]-two signals that represent the CS and US in these cells. Conditioning requires that the CS and US be paired within a narrow time window and in the appropriate sequence. AC shows an analogous sequence preference: It is more effectively activated when a pulse of Ca2+ precedes a pulse of 5-HT than when the 5-HT precedes Ca2+. One mechanism that contributes to this sequence preference is that Ca2+/calmodulin binding to AC accelerates the rate of AC activation by receptor-Gs. We have identified two additional properties of AC activation that would cause pairing with Ca2+ preceding 5-HT to be more effective than simultaneous pairing or pairing with the reciprocal sequence: (1) Activation of Aplysia AC by a Ca2+ pulse rose with a delay compared with activation by a 5-HT pulse. (2) A late pulse of Ca2+, which arrived after 5-HT, acted, via calmodulin, to accelerate the decay of AC activation by receptor-Gs. Together, these activation properties of AC may contribute to the CS-US sequence requirement of classical conditioning.

To assess the relationship between two phenotypes in an extremely well-characterized population of personality disorder patients-impulsive aggression and prolactin response to fenfluramine-and tryptophan hydroxylase (TPH) genotype, TPH genotype (at an intronic polymorphic site) and prolactin response to fenfluramine were assessed in 40 Caucasian patients with personality disorder. Impulsive aggression was assessed by using the Buss-Durkee Hostility Inventory (BDHI). Twenty-one male patients with the "LL" genotype had higher BDHI scores than men with the "UL" or the "UU" genotype. No relationship between genotype and prolactin response to fenfluramine was found. It was concluded that impulsive-aggressive behavior in male personality disorder patients may be associated with the TPH genotype.

To assess patterns of hearing loss and asymmetry in major depressive disorder (MDD), pure-tone and brief-click audiometric thresholds were measured in 59 inpatients with MDD and 40 normal control subjects. For both tasks, patients had higher bilateral thresholds, with marked hearing loss for the highest pure-tone frequency. At lower frequencies, patients displayed significant asymmetry, with poorer hearing in the left ear. After ECT, patients maintained the bilateral hearing losses; however, the baseline asymmetry resolved. These findings suggest that bilateral hearing loss may be a stable characteristic in severe depression. Poorer left ear pure-tone hearing may be present during the depressed state. The baseline asymmetry in audiometric deficits suggests right-hemisphere dysfunction in severe MDD.

Studies in Aplysia and Drosophila have suggested that Ca2+/calmodulin-sensitive adenylyl cyclase may act as a site of convergence for the cellular representations of the conditioned stimulus (Ca2+ influx) and unconditioned stimulus (facilitatory transmitter) during elementary associative learning. This hypothesis predicts that the rise in intracellular free Ca2+ concentration produced by spike activity during the conditioned stimulus will cause an increase in the activity of adenylyl cyclase. However, published values for the Ca2+ sensitivity of Ca2+/calmodulin-sensitive adenylyl cyclase in mammals and in Drosophila vary widely. The difficulty in evaluating whether adenylyl cyclase would be activated by physiological elevations in intracellular Ca2+ levels is in part a consequence of the use of Ca2+/EGTA buffers, which are prone to several types of errors. Using a procedure that minimizes these errors, we have quantified the Ca2+ sensitivity of adenylyl cyclase in membranes from Aplysia, Drosophila, and rat brain with purified species-specific calmodulins. In all three species, adenylyl cyclase was activated by an increase in free Ca2+ concentration in the range caused by spike activity. Ca2+ sensitivity was dependent on both calmodulin concentration and Mg2+ concentration. Mg2+ raised the threshold for adenylyl cyclase activation by Ca2+ but also acted synergistically with Ca2+ to activate maximally adenylyl cyclase.

Cellular experiments have suggested that during classical conditioning of the gill and siphon withdrawal reflex of Aplysia, adenylyl cyclase may serve as a molecular site of convergence for Ca2+ and serotonin (5-hydroxytryptamine; 5-HT), the cellular representations of the conditioned and unconditioned stimuli (CS and US). We explored the possible molecular basis of the behavioral requirement that the CS and US be paired within a narrow time window and in the appropriate order. To examine the temporal interactions of brief pulses of Ca2+ and 5-HT in stimulating Aplysia neural cyclase, we used a perfused-membrane cyclase assay. When brief pulses of Ca2+ and 5-HT were paired, cyclase activation depended upon the sequence of the pulses: peak cyclase activation was greater when the Ca2+ pulse immediately preceded the 5-HT pulse. Examination of the rising phase of 5-HT stimulation suggested that a Ca2+ prepulse might accelerate the onset of activation by 5-HT, without affecting the final level of activation achieved with prolonged 5-HT exposure. The observed interactions between Ca2+ and transmitter in activating cyclase could contribute importantly to the temporal requirements of conditioning for CS-US pairing.

The Drosophila memory mutant rutabaga (rut) has been previously shown to have a defective subpopulation (or functional state) of the enzyme adenylate cyclase. We report here that the reduced adenylate cyclase activity is also associated with a defective responsiveness of the enzyme to forskolin. Forskolin activation isotherms of the enzyme in normal membranes reveal low- and high-affinity forskolin-interacting components; the residual enzyme in the mutant shows a smaller proportion of the high-affinity response. In addition, in mutant membrane preparations, forskolin fails to shift the Km of the enzyme for free Mg2+ and for MgATP, in contrast to the situation in the normal tissue. The defect in the responsiveness to forskolin in rut is even more pronounced in a Lubrol-solubilized enzyme preparation, and is due to intrinsic properties of the cyclase system rather than to the absence (or presence) of a soluble, or detergent solubilized, factor in rut. The reduced forskolin responsiveness maps to the X chromosomal segment 12F5-6 to 13A1-5, within the region previously reported to span the locus that controls both the abortive memory and the lack of Ca2+-stimulation of adenylate cyclase in rut17. The possible relevance of the findings to postulated molecular mechanisms of short-term memory formation is discussed.

During short-term sensitization, a simple form of nonassociative learning in Aplysia, the presentation of a single brief noxious stimulus results in enhancement of the defensive withdrawal reflex lasting minutes to tens of minutes. This behavioral plasticity involves presynaptic facilitation of synaptic transmission from the mechanosensory neurons that mediate the reflex to their central target cells. This facilitation is due to cAMP-dependent protein phosphorylation. To determine whether the time course of presynaptic facilitation might be due to a persistent increase in activity of adenylate cyclase (EC 4.6.1.1) itself, persistence of the transmitter, or yet other processes, we developed a perfused-membrane method to analyze the time course of activation of adenylate cyclase by transient stimuli. After stimulation by a pulse of stimulatory transmitter, activation of adenylate cyclase decayed within 60 sec. This finding indicates that the enzyme does not remain persistently active in the absence of transmitter and suggests that short-term retention is likely to be due to other mechanisms. Possible additional mechanisms include continued activation of the cyclase by transmitter, cellular factors extrinsic to the cyclase that prolong the time course of its activation, and persistence of processes downstream from the cyclase.

Two experimental approaches--the cellular and the neurogenetic--to the study of molecular mechanisms of elementary memory implicate the cyclic AMP cascade in general, and adenylate cyclase in particular, in the processes of acquisition and short-term memory. Models of learning and memory should account for four basic phenomena: persistence of memory, stimulus convergence, temporal specificity and memory decay. These phenomena thus place constraints on the structure and operation of any postulated memory apparatus. The relevant experimental data derived from the study of memory mutants in Drosophila and of the gill and siphon withdrawal reflex in Aplysia are discussed and analyzed in light of the above mentioned constraints.