Limbic system plasticity after electroacupuncture intervention in knee osteoarthritis rats.

Knee osteoarthritis (KOA) is characterized by debilitating pain. Electroacupuncture (EA), a traditional Chinese medical therapy, has shown promise in KOA pain management. This study investigated the therapeutic potential of EA in KOA and its impact on limbic system neural plasticity. Sixteen rats were randomly assigned into two groups: EA group and sham-EA group. EA or sham-EA interventions were administered at acupoints ST32 (Futu) and ST36 (Zusanli) for three weeks. Post-intervention resting-state fMRI was scanned, assessing parameters including Amplitude of low frequency fluctuations (ALFF), regional homogeneity (ReHo), functional connectivity (FC) and nodal characterizations of network within limbic system. The results showed that EA was strategically directed towards the limbic system, resulting in discernible alterations in neural activity, FC, and network characteristics. Our findings demonstrate that EA had a significant impact on the limbic system neural plasticity in rats with KOA, presenting a novel nonpharmacological approach for KOA treatment.

Multimodal quantitative magnetic resonance imaging of the thalamus in tinnitus patients with different outcomes after sound therapy.

AIMS: This study systematically investigated structural and functional alterations in the thalamus and its subregions using multimodal magnetic resonance imaging (MRI) and examined its clinical relevance in tinnitus patients with different outcomes after sound therapy (narrowband noise). METHODS: In total, 60 patients with persistent tinnitus and 57 healthy controls (HCs) were recruited. Based on treatment efficacy, 28 patients were categorized into the effective group and 32 into the ineffective group. Five MRI measurements of the thalamus and its seven subregions, including gray matter volume, fractional anisotropy, fractional amplitude of low-frequency fluctuation, and functional connectivity (FC), were obtained for each participant and compared between the groups. RESULTS: Patients in both the groups exhibited widespread functional and diffusion abnormalities in the whole thalamus and several subregions, with more obvious changes observed in the effective group. All tinnitus patients had abnormal FC compared with the HCs; FC differences between the two patient groups were only observed in the striatal network, auditory-related cortex, and the core area of the limbic system. We combined the multimodal quantitative thalamic alterations and used it as an imaging indicator to evaluate prognosis before sound therapy and achieved a sensitivity of 71.9% and a specificity of 85.7%. CONCLUSION: Similar patterns of thalamic alterations were identified in tinnitus patients with different outcomes, with more obvious changes observed in the effective group. Our findings support the tinnitus generation hypothesis of frontostriatal gating system dysfunction. A combination of multimodal quantitative thalamic properties may be used as indicators to predict tinnitus prognosis before sound therapy.

The Cortico-Limbo-Thalamo-Cortical Circuits: An Update to the Original Papez Circuit of the Human Limbic System.

The Papez circuit, first proposed by James Papez in 1937, is a circuit believed to control memory and emotions, composed of the cingulate cortex, entorhinal cortex, parahippocampal gyrus, hippocampus, hypothalamus, and thalamus. Pursuant to James Papez, Paul Yakovlev and Paul MacLean incorporated the prefrontal/orbitofrontal cortex, septum, amygdalae, and anterior temporal lobes into the limbic system. Over the past few years, diffusion-weighted tractography techniques revealed additional limbic fiber connectivity, which incorporates multiple circuits to the already known complex limbic network. In the current review, we aimed to comprehensively summarize the anatomy of the limbic system and elaborate on the anatomical connectivity of the limbic circuits based on the published literature as an update to the original Papez circuit.

Analysis of the extent of limbic system changes in multiple sclerosis using FreeSurfer and voxel-based morphometry approaches.

BACKGROUND AND PURPOSE: The limbic brain is involved in diverse cognitive, emotional, and autonomic functions. Injury of the various parts of the limbic system have been correlated with clinical deficits in MS. The purpose of this study was to comprehensively examine different regions of the subcortical limbic system to assess the extent of damage within this entire system as it may be pertinent in correlating with specific aspects of cognitive and behavioral dysfunction in MS by using a fully automated, unbiased segmentation approach. METHODS: Sixty-seven subjects were included in this study, including 52 with multiple sclerosis (MS) and 15 healthy controls. Only patients with stable MS disease, without any relapses, MRI activity, or disability progression were included. Subcortical limbic system segmentation was performed using the FreeSurfer pipeline ScLimbic, which provides volumes for fornix, mammillary bodies, hypothalamus, septal nuclei, nucleus accumbens, and basal forebrain. Hippocampus and anterior thalamic nuclei were added as additional components of the limbic circuitry, also segmented through FreeSurfer. Whole limbic region mask was generated by combining these structures and used for Voxel-based morphometry (VBM) analysis. RESULTS: The mean [95% confidence interval] of the total limbic system volume was lower (0.22% [0.21-0.23]) in MS compared to healthy controls (0.27%, [0.25-0.29], p < .001). Pairwise comparisons of individual limbic regions between MS and controls was significant in the nucleus accumbens (0.046%, [0.043-0.050] vs. 0.059%, [0.051-0.066], p = .005), hypothalamus (0.062%, [0.059-0.065] vs. 0.074%, [0.068-0.081], p = .001), basal forebrain (0.038%, [0.036-0.040] vs. 0.047%, [0.042-0.051], p = .001), hippocampus (0.47%, [0.45-0.49] vs. 0.53%, [0.49-0.57], p = .004), and anterior thalamus (0.077%, [0.072-0.082] vs. 0.093%, [0.084-0.10], p = .001) after Bonferroni correction. Volume of several limbic regions was significantly correlated with T2 lesion burden and brain parenchymal fraction (BPF). Multiple regression model showed minimal influence of BPF on limbic brain volume and no influence of other demographic and disease state variables. VBM analysis showed cluster differences in the fornix and anterior thalamic nuclei at threshold p < 0.05 after adjusting for covariates but the results were insignificant after family-wise error corrections. CONCLUSIONS: The results show evidence that brain volume loss is fairly extensive in the limbic brain. Given the significance of the limbic system in many disease states including MS, such volumetric analyses can be expanded to studying cognitive and emotional disturbances in larger clinical trials. FreeSurfer ScLimbic pipeline provided an efficient and reliable methodology for examining many of the subcortical structures related to the limbic brain.

The effectiveness of the combined transcranial direct current stimulation (tDCS) and tailor-made notched music training (TMNMT) on psychoacoustic, psychometric, and cognitive indices of tinnitus patients.

PURPOSE: Tinnitus network(s) consists of pathways in the auditory cortex, frontal cortex, and the limbic system. The cortical hyperactivity caused by tinnitus may be suppressed by neuromodulation techniques. Due to the lack of definitive treatment for tinnitus and limited usefulness of the individual methods, in this study, a combination of transcranial direct current stimulation (tDCS) over the dorsolateral prefrontal cortex (DLPFC) and tailor-made notched music training (TMNMT) was used. MATERIAL AND METHODS: In this descriptive-analytic study, 26 patients with chronic unilateral tinnitus of the right ear were randomly divided into the clinical trial group (CTG) and the control group (CG). In both groups, six sessions of tDCS with 2 mA intensity for 20 min, with anode on F4 and cathode on F3, were conducted. Simultaneous with tDCS sessions, and based on TMNMT, the participant was asked to listen passively for 120 min/day, to a CD containing her/his favorite music with a proper notch applied in its spectrum according to the individual's tinnitus The treatment outcome was measured by, psychoacoustic (loudness-matching), psychometric (awareness, loudness and annoyance Visual Analogue Scale (VAS) scores, and Tinnitus Handicap Inventory (THI)) scores, and cognitive assessments (randomized dichotic digits test (RDDT) and dichotic auditory-verbal memory test (DAVMT)). Repeated measurement test was used for statistical analyses. RESULTS: In the CTG, the tinnitus loudness and annoyance VAS scores, and THI were reduced significantly (p = 0.001). In addition, the DAVMT and RDDT scores were enhanced (p = 0.001). Such changes were not observed in the CG (p > 0.05). CONCLUSION: The combination of tDCS and TMNMT led to a reduction in the loudness, awareness, annoyance, and also disability induced by tinnitus in CTG. Furthermore, this method showed an improvement of cognitive functions (auditory divided attention, selective attention and working memory) in the CTG.

Neuroimmune and Mu-Opioid Receptor Alterations in the Mesocorticolimbic System in a Sex-Dependent Inflammatory Pain-Induced Alcohol Relapse-Like Rat Model.

Evidence concerning the role of alcohol-induced neuroinflammation in alcohol intake and relapse has increased in the last few years. It is also proven that mu-opioid receptors (MORs) mediate the reinforcing properties of alcohol and, interestingly, previous research suggests that neuroinflammation and MORs could be related. Our objective is to study neuroinflammatory states and microglial activation, together with adaptations on MOR expression in the mesocorticolimbic system (MCLS) during the abstinence and relapse phases. To do so, we have used a sex-dependent rat model of complete Freund's adjuvant (CFA)-induced alcohol deprivation effect (ADE). Firstly, our results confirm that only CFA-treated female rats, the only experimental group that showed relapse-like behavior, exhibited specific alterations in the expression of phosphorylated NFκB, iNOS, and COX2 in the PFC and VTA. More interestingly, the analysis of the IBA1 expression revealed a decrease of the microglial activation in PFC during abstinence and an increase of its expression in the relapse phase, together with an augmentation of this activation in the NAc in both phases that only occur in female CFA-treated rats. Additionally, the expression of IL1ß also evidenced these dynamic changes through these two phases following similar expression patterns in both areas. Furthermore, the expression of the cytokine IL10 showed a different profile than that of IL1ß, indicating anti-inflammatory processes occurring only during abstinence in the PFC of CFA-female rats but neither during the reintroduction phase in PFC nor in the NAc. These data indicate a downregulation of microglial activation and pro-inflammatory processes during abstinence in the PFC, whereas an upregulation can be observed in the NAc during abstinence that is maintained during the reintroduction phase only in CFA-female rats. Secondly, our data reveal a correlation between the alterations observed in IL1ß, IBA1 levels, and MOR levels in the PFC and NAc of CFA-treated female rats. Although premature, our data suggest that neuroinflammatory processes, together with neural adaptations involving MOR, might play an important role in alcohol relapse in female rats, so further investigations are warranted.

Susceptibility of subregions of prefrontal cortex and corpus callosum to damage by high-dose oxytocin-induced labor in male neonatal mice.

Induction and augmentation of labor is one of the most common obstetrical interventions. However, this intervention is not free of risks and could cause adverse events, such as hyperactive uterine contraction, uterine rupture, and amniotic-fluid embolism. Our previous study using a new animal model showed that labor induced with high-dose oxytocin (OXT) in pregnant mice resulted in massive cell death in selective brain regions, specifically in male offspring. The affected brain regions included the prefrontal cortex (PFC), but a detailed study in the PFC subregions has not been performed. In this study, we induced labor in mice using high-dose OXT and investigated neonatal brain damage in detail in the PFC using light and electron microscopy. We found that TUNEL-positive or pyknotic nuclei and Iba-1-positive microglial cells were detected more abundantly in infralimbic (IL) and prelimbic (PL) cortex of the ventromedial PFC (vmPFC) in male pups delivered by OXT-induced labor than in the control male pups. These Iba-1-positive microglial cells were engulfing dying cells. Additionally, we also noticed that in the forceps minor (FMI) of the corpus callosum (CC), the number of TUNEL-positive or pyknotic nuclei and Iba-1-positive microglial cells were largely increased and Iba-1-positive microglial cells phagocytosed massive dying cells in male pups delivered by high-dose OXT-induced labor. In conclusion, IL and PL of the vmPFC and FMI of the CC, were susceptible to brain damage in male neonates after high-dose OXT-induced labor.

Migraine attacks as a result of hypothalamic loss of control.

Migraine is a complex neurological disorder affecting approximately 12% of the population. The pathophysiology is not yet fully understood, however the clinical features of the disease, such as the cyclic behaviour of attacks and vegetative symptoms, suggest a prominent role of the hypothalamus. Previous research has observed neuronal alterations at different time points during the migraine interval, specifically just before the headache is initiated. We therefore aimed to assess the trajectory of migraineurs' brain activity over an entire migraine cycle. Using functional magnetic resonance imaging (fMRI) with pseudo-continuous arterial spin labelling (ASL), we designed a longitudinal intra-individual study to detect the rhythmicity of (1) the cerebral perfusion and (2) the hypothalamic connectivity over an entire migraine cycle. Twelve episodic migraine patients were examined in 82 sessions during spontaneous headache attacks with follow-up recordings towards the next attack. We detected cyclic changes of brain perfusion in the limbic circuit (insula and nucleus accumbens), with the highest perfusion during the headache attack. In addition, we found an increase of hypothalamic connectivity to the limbic system over the interictal interval towards the attack, then collapsing during the headache phase. The present data provide strong evidence for the predominant role of the hypothalamus in generating migraine attacks. Due to a genetically-determined cortical hyperexcitability, migraineurs are most likely characterised by an increased susceptibility of limbic neurons to the known migraine trigger. The hypothalamus as a metronome of internal processes is suggested to control these limbic circuits: migraine attacks may occur as a result of the hypothalamus losing control over the limbic system. Repetitive psychosocial stress, one of the leading trigger factors reported by patients, might make the limbic system even more vulnerable and lead to a premature triggering of a migraine attack. Potential therapeutic interventions are therefore suggested to strengthen limbic circuits with dedicated medication or psychological approaches.

The paraventricular thalamus provides a polysynaptic brake on limbic CRF neurons to sex-dependently blunt binge alcohol drinking and avoidance behavior in mice.

Bed nucleus of the stria terminalis (BNST) neurons that synthesize corticotropin-releasing factor (CRF) drive binge alcohol drinking and anxiety. Here, we found that female C57BL/6J mice binge drink more than males and have greater basal BNSTCRF neuron excitability and synaptic excitation. We identified a dense VGLUT2 + synaptic input from the paraventricular thalamus (PVT) that releases glutamate directly onto BNSTCRF neurons but also engages a large BNST interneuron population to ultimately inhibit BNSTCRF neurons, and this polysynaptic PVTVGLUT2-BNSTCRF circuit is more robust in females than males. Chemogenetic inhibition of the PVTBNST projection promoted binge alcohol drinking only in female mice, while activation reduced avoidance behavior in both sexes. Lastly, repeated binge drinking produced a female-like phenotype in the male PVT-BNSTCRF excitatory synapse without altering the function of PVTBNST neurons per se. Our data describe a complex, feedforward inhibitory PVTVGLUT2-BNSTCRF circuit that is sex-dependent in its function, behavioral roles, and alcohol-induced plasticity.

Phenotypical predictors of pregnancy-related restless legs syndrome and their association with basal ganglia and the limbic circuits.

Restless legs syndrome (RLS) in pregnancy is a common disorder with a multifactorial etiology. A neurological and obstetrical cohort of 308 postpartum women was screened for RLS within 1 to 6 days of childbirth and 12 weeks postpartum. Of the 308 young mothers, 57 (prevalence rate 19%) were identified as having been affected by RLS symptoms in the recently completed pregnancy. Structural and functional MRI was obtained from 25 of these 57 participants. A multivariate two-window algorithm was employed to systematically chart the relationship between brain structures and phenotypical predictors of RLS. A decreased volume of the parietal, orbitofrontal and frontal areas shortly after delivery was found to be linked to persistent RLS symptoms up to 12 weeks postpartum, the symptoms' severity and intensity in the most recent pregnancy, and a history of RLS in previous pregnancies. The same negative relationship was observed between brain volume and not being married, not receiving any iron supplement and higher numbers of stressful life events. High cortisol levels, being married and receiving iron supplements, on the other hand, were found to be associated with increased volumes in the bilateral striatum. Investigating RLS symptoms in pregnancy within a brain-phenotype framework may help shed light on the heterogeneity of the condition.

Voluntary binge-patterned alcohol drinking and sex-specific influences on monoamine-related neurochemical signatures in the mouse gut and brain.

BACKGROUND: Altered monoamine (i.e., serotonin, dopamine, and norepinephrine) activity following episodes of alcohol abuse plays key roles not only in the motivation to ingest ethanol, but also physiological dysfunction related to its misuse. Although monoamine activity is essential for physiological processes that require coordinated communication across the gut-brain axis (GBA), relatively little is known about how alcohol misuse may affect monoamine levels across the GBA. Therefore, we evaluated monoamine activity across the mouse gut and brain following episodes of binge-patterned ethanol drinking. METHODS: Monoamine and select metabolite neurochemical concentrations were analyzed by ultra-high-performance liquid chromatography in gut and brain regions of female and male C57BL/6J mice following "Drinking in the Dark" (DID), a binge-patterned ethanol ingestion paradigm. RESULTS: First, we found that alcohol access had an overall small effect on gut monoamine-related neurochemical concentrations, primarily influencing dopamine activity. Second, neurochemical patterns between the small intestine and the striatum were correlated, adding to recent evidence of modulatory activity between these areas. Third, although alcohol access robustly influenced activity in brain areas in the mesolimbic dopamine system, binge exposure also influenced monoaminergic activity in the hypothalamic region. Finally, sex differences were observed in the concentrations of neurochemicals within the gut, which was particularly pronounced in the small intestine. CONCLUSION: Together, these data provide insights into the influence of alcohol abuse and biological sex on monoamine-related neurochemical changes across the GBA, which could have important implications for GBA function and dysfunction.

Mental Health from Medical School to Medical Practice: Finding a Path Forward.

Medical students, residents, and practicing physicians experience high burnout, depression, and suicide rates, and the COVID-19 pandemic has exacerbated stress for many.1-6 While laudable, current well-being efforts appear insufficient to meet the challenges that so many are facing. This essay explores approaches that individuals and organizations can take to promote mental health and well-being from medical school to practice.

Roles of central orexinergic system on cardiovascular function and acupuncture on intervention of cardiovascular risk: Orexinergic system mediate the role of acupuncture?

Central orexinergic system contributes to the regulation of cardiovascular function. Orexinergic neurons receiving projections of nerve fibers from multiple structures of brain which involved in control and regulation of cardiovascular function locate in hypothalamus, and their axon terminals widely project to various central structures where orexins receptors are expressed. Here, we summarize the present knowledge that describes the influence of central orexinergic system on cardiovascular activity, the relevance of dysfunction in central orexinergic system with hypertension and psychological stress induced cardiovascular reactivity which are serious risk factors for cardiovascular disease and cardiovascular death. We propose that central orexinergic system may be potentially important targets for the prevention of cardiovascular disease and cardiovascular death, and different orexinergic system involved neuronal circuits may be involved in distinct cardiovascular functions. Acupuncture having bidirectional regulatory ability and a much lower incidence of side effects can prevent disease. We review the improvement of acupuncture on hypertension and psychological stress induced cardiovascular reactivity. We think that acupuncture intervenes hypertension and psychological stress induced cardiovascular reactivity to prevent cardiovascular disease and cardiovascular death. We also summarize relation between acupuncture and central orexinergic system. We propose a hypothesis that acupuncture improve hypertension and psychological stress induced cardiovascular reactivity through regulating central orexinergic system. The knowledge is beneficial for the development of potential therapeutic targets and methods to prevent cardiovascular disease and cardiovascular death.

Altered functional connectivity between hypothalamus and limbic system in fibromyalgia.

The hypothalamus links the nervous system to the endocrine system and plays a crucial role in maintaining the human body's homeostasis. This study aims to investigate the resting state functional connectivity (rsFC) changes of the hypothalamus in fibromyalgia patients. 24 Fibromyalgia patients and 24 matched healthy controls (HCs) were recruited. Resting state fMRI data were collected from the fibromyalgia patients and HC's. Fibromyalgia patients went through a second scan after 12 weeks of Tai Chi mind-body intervention. Data analysis showed that fibromyalgia patients displayed less medial hypothalamus (MH) rsFC with the thalamus and amygdala when compared to the functional connectivity in the HCs. After the Tai Chi mind-body intervention, fibromyalgia patients showed increased MH rsFC with the thalamus and amygdala accompanied by clinical improvement. Effective connectivity analysis showed disrupted MH and thalamus interaction in the fibromyalgia patients, which was altered by mind-body exercise. Our findings suggest that fibromyalgia is associated with altered functional connectivity within the diencephalon and limbic system. Elucidating the roles of the diencephalon and limbic system in the pathophysiology and development of fibromyalgia may facilitate the development of a new biomarker and effective treatment methods for this prevalent disorder.Trial Registration ClinicalTrials.gov, NCT02407665. Registered: 3 April 2015, https://clinicaltrials.gov/ct2/show/NCT02407665?term=NCT02407665&draw=2&rank=1.

Limbic cortico-striato-thalamo-cortical functional connectivity in drug-naïve patients of obsessive-compulsive disorder.

BACKGROUND: The pathophysiology of obsessive-compulsive disorder (OCD) remains unclear despite extensive neuroimaging work on the disorder. Exposure to medication and comorbid mental disorders can confound the results of OCD studies. The goal of this study was to explore differences in brain functional connectivity (FC) within the cortico-striato-thalamo-cortical (CSTC) loop of drug-naïve and drug-free OCD patients and healthy controls (HCs). METHODS: A total of 29 drug-naïve OCD patients, 22 drug-free OCD patients, and 25 HCs matched on age, gender and education level underwent functional magnetic resonance imaging scanning at resting state. Seed-based connectivity analyses were conducted among the three groups. The Yale Brown Obsessive Compulsive Scale and clinical inventories were used to assess the clinical symptoms. RESULTS: Compared with HCs, the drug-naïve OCD patients had reduced FC within the limbic CSTC loop. In the drug-naïve OCD participants, we also found hyperconnectivity between the supplementary motor area and ventral and dorsal putamen (p < 0.05, corrected for multiple comparisons). CONCLUSIONS: Exposure to antidepressants such as selective serotonin reuptake inhibitors may affect the function of some brain regions. Future longitudinal studies could help to reveal the pharmacotherapeutic mechanisms in these loops.

Functional constipation is associated with alterations in thalamo-limbic/parietal structural connectivity.

BACKGROUND: Functional constipation (FCon) is a common functional gastrointestinal disorder (FGID) with a high prevalence in clinical practice. Previous studies have identified that FCon is associated with functional and structural alterations in the primary brain regions involved in emotional arousal processing, sensory processing, somatic/motor-control, and self-referential processing. However, whether FCon is associated with abnormal structural connectivity (SC) among these brain regions remains unclear. METHODS: We selected the brain regions with functional and structural abnormalities as seed regions and employed diffusion tensor imaging (DTI) with probabilistic tractography to investigate SC changes in 29 patients with FCon and 31 healthy controls (HC). KEY RESULTS: Results showed lower fractional anisotropy (FA) in the fibers connecting the thalamus, a region involved in sensory processing, with the amygdala (AMY), hippocampal gyrus (HIPP), precentral (PreCen) and postcentral gyrus (PostCen), supplementary motor area (SMA) and precuneus in patients with FCon compared with HC. FCon had higher mean diffusivity (MD) and radial diffusivity (RD) in the thalamus connected to the AMY and HIPP. In addition, FCon had significantly increased RD of the thalamus-SMA tract. Sensation of incomplete evacuation was negatively correlated with FA of the thalamus-PostCen and thalamus-HIPP tracts, and there was a negative correlation between difficulty of defecation and FA of the thalamus-SMA tract. CONCLUSIONS AND INFERENCES: These findings reflected that FCon is associated with alterations in SC between the thalamus and limbic/parietal cortex, highlighting the integrative role of the thalamus in brain structural network.

Targeting the Endocannabinoid System in Borderline Personality Disorder: Corticolimbic and Hypothalamic Perspectives.

Borderline Personality Disorder (BPD) is a chronic debilitating psychiatric disorder characterized mainly by emotional instability, chaotic interpersonal relationships, cognitive disturbance (e.g., dissociation and suicidal thoughts) and maladaptive behaviors. BPD has a high rate of comorbidity with other mental disorders and a high burden on society. In this review, we focused on two compromised brain regions in BPD - the hypothalamus and the corticolimbic system, emphasizing the involvement and potential contribution of the endocannabinoid system (ECS) to improvement in symptoms and coping. The hypothalamus-regulated endocrine axes (hypothalamic pituitary - gonadal, thyroid & adrenal) have been found to be dysregulated in BPD. There is also substantial evidence for limbic system structural and functional changes in BPD, especially in the amygdala and hippocampus, including cortical regions within the corticolimbic system. Extensive expression of CB1 and CB2 receptors of the ECS has been found in limbic regions and the hypothalamus. This opens new windows of opportunity for treatment with cannabinoids such as cannabidiol (CBD) as no other pharmacological treatment has shown long-lasting improvement in the BPD population to date. This review aims to show the potential role of the ECS in BPD patients through their most affected brain regions, the hypothalamus and the corticolimbic system. The literature reviewed does not allow for general indications of treatment with CBD in BPD. However, there is enough knowledge to indicate a treatment ratio of a high level of CBD to a low level of THC. A randomized controlled trial investigating the efficacy of cannabinoid based treatments in BPD is warranted.

Title: Injury characteristics of the Papez circuit in patients with diffuse axonal injury: a diffusion tensor tractography study.

We investigate the characteristics of injury of four portions of the Papez circuit in patients with diffuse axonal injury (DAI), using diffusion tensor tractography (DTT). Thirty-four consecutive patients with DAI and 30 normal control subjects were recruited. Four portions of the Papez circuit were reconstructed: the fornix, cingulum, thalamocingulate tract, and mammillothalamic tract. Analysis of DTT parameters [fractional anisotropy (FA) and tract volume (TV)] and configuration (narrowing, discontinuation, or non-reconstruction) was performed for each portion of the Papez circuit. The Memory Assessment Scale (MAS) was used for the estimation of cognitive function. In the group analysis, decreased fractional anisotropy and tract volume of the entire Papez circuit were observed in the patient group compared with the control group (p < 0.05). In the individual analysis, all four portions of the Papez circuit were injured in terms of DTT parameters or configuration. Positive correlation was observed between TV of the fornix and short-term memory on MAS r = 0.618, p < 0.05), and between FA of the fornix and total memory on MAS (r = 0.613, p < 0.05). We found that all four portions of the Papez circuit in the patient group were vulnerable to DAI, and among four portions of the Papez circuit, the fornix was the most vulnerable portion in terms of injury incidence and severity.

Cerebellar-limbic neurocircuit is the novel biosignature of physio-cognitive decline syndrome.

Both physical and cognitive deficits occur in the aging process. We operationally defined the phenomenon as physio-cognitive decline syndrome (PCDS) and aimed to decipher its corresponding neuroanatomy patterns and neurocircuit. High resolution 3T brain magnetic resonance imaging (MRI) images from a community-dwelling longitudinal aging cohort were analysed. PCDS was defined as weakness (handgrip strength) and/or slowness (gait speed) concomitant with impairment in any cognitive domain (defined by 1.5 standard deviation below age, sex-matched norms), but without dementia or disability. Among 1196 eligible ≥ 50-year-old (62±9 years, 47.6%men) subjects, 15.9% had PCDS. Compared to the other participants, individuals with PCDS had significantly lower gray-matter volume (GMV) in the bilateral amygdala and thalamus, right hippocampus, right temporo-occipital cortex, and left cerebellum VI and V regions. The regions of reduced GMV in people with PCDS were similar between the middle-aged and older adults; whereas larger clusters with more extensive GMV-depleted regions were observed in ≥65-year-olds with PCDS. Diffusion-weighted tractography showed disrupted hippocampus-amygdala-cerebellum connections in subjects with PCDS. The neuroanatomic characteristics revealed by this study provide evidence for pathophysiological processes associated with concomitant physio-cognitive decline in the elderly. This neurocircuit might constitute a target for future preventive interventions.

Offensive Behavior, Striatal Glutamate Metabolites, and Limbic-Hypothalamic-Pituitary-Adrenal Responses to Stress in Chronic Anxiety.

Variations in anxiety-related behavior are associated with individual allostatic set-points in chronically stressed rats. Actively offensive rats with the externalizing indicators of sniffling and climbing the stimulus and material tearing during 10 days of predator scent stress had reduced plasma corticosterone, increased striatal glutamate metabolites, and increased adrenal 11-dehydrocorticosterone content compared to passively defensive rats with the internalizing indicators of freezing and grooming, as well as to controls without any behavioral changes. These findings suggest that rats that display active offensive activity in response to stress develop anxiety associated with decreased allostatic set-points and increased resistance to stress.