Fronto-limbic Pathways Research Articles

The First “Hit” to the Endocannabinoid System? Associations Between Prenatal Cannabis Exposure and Frontolimbic White Matter Pathways in Children

BackgroundCannabis is the most used federally illicit substance among pregnant people in the United States. However, emerging preclinical data show that a significant portion of cannabis constituents, such as Δ9-tetrahydrocannabinol and its bioactive metabolites, readily cross the placenta and accumulate in the fetal brain, disrupting neurodevelopment. Recent research using the Adolescent Brain Cognitive Development (ABCD) Study cohort has linked prenatal cannabis exposure (PCE) to greater neurobehavioral problems and lower total gray and white matter volume in children. Here, we examined the impact of PCE on frontolimbic white matter pathways that are critical for cognitive- and emotion-related functioning, show a high density of cannabinoid receptors, and are susceptible to cannabis exposure during other periods of rapid neurodevelopment (e.g., adolescence). MethodsThis study included 11,530 children (mean ± SD age = 118.99 ± 7.49 months; 47% female) from the ABCD Study cohort. Linear mixed-effects models were used to examine the effects of caregiver-reported PCE on fractional anisotropy of 10 frontolimbic pathways (5 per hemisphere). ResultsPCE was associated with lower fractional anisotropy of the right (β = −0.005, p < .001) and left (β = −0.003, p = .007) fornix, and these results remained significant after adjusting for a variety of covariates, multiple comparisons, fractional anisotropy of all fibers, and using a quality-control cohort only. ConclusionsIn sum, we demonstrated small, yet reliable, effects of PCE on white matter integrity during childhood, particularly in the fornix, which plays a crucial role in emotion- and memory-related processes. Future studies are needed to understand the impacts of small changes in brain structure or function on neurodevelopment and risk of neurobehavioral problems.

Prenatal exposure to maternal social disadvantage and psychosocial stress and neonatal white matter connectivity at birth

Early life adversity (social disadvantage and psychosocial stressors) is associated with altered microstructure in fronto-limbic pathways important for socioemotional development. Understanding when these associations begin to emerge may inform the timing and design of preventative interventions. In this longitudinal study, 399 mothers were oversampled for low income and completed social background measures during pregnancy. Measures were analyzed with structural equation analysis resulting in two latent factors: social disadvantage (education, insurance status, income-to-needs ratio [INR], neighborhood deprivation, and nutrition) and psychosocial stress (depression, stress, life events, and racial discrimination). At birth, 289 healthy term-born neonates underwent a diffusion MRI (dMRI) scan. Mean diffusivity (MD) and fractional anisotropy (FA) were measured for the dorsal and inferior cingulum bundle (CB), uncinate, and fornix using probabilistic tractography in FSL. Social disadvantage and psychosocial stress were fitted to dMRI parameters using regression models adjusted for infant postmenstrual age at scan and sex. Social disadvantage, but not psychosocial stress, was independently associated with lower MD in the bilateral inferior CB and left uncinate, right fornix, and lower MD and higher FA in the right dorsal CB. Results persisted after accounting for maternal medical morbidities and prenatal drug exposure. In moderation analysis, psychosocial stress was associated with lower MD in the left inferior CB among the lower-to-higher socioeconomic status (SES) (INR ≥ 200%) group, but not the extremely low SES (INR < 200%) group. Increasing access to social welfare programs that reduce the burden of social disadvantage and related psychosocial stressors may be an important target to protect fetal brain development in fronto-limbic pathways.

Impact of Childhood Trauma Exposure, Genetic Variation in Endocannabinoid Signaling, and Anxiety on Frontolimbic Pathways in Children.

Introduction: The endocannabinoid (eCB) system plays a key role in modulating brain development, including myelination processes. Recent studies link a common variant (C385A, rs324420) in the fatty acid amide hydrolase (FAAH) gene to higher circulating eCB levels, lower anxiety, and altered frontolimbic development. Frontolimbic pathways, which demonstrate a protracted maturational course across childhood and adolescence, are associated with anxiety, and are vulnerable to environmental stressors such as trauma exposure. Here, we examined the impact of trauma exposure, FAAH genotype, and anxiety on frontolimbic white matter microstructure in children. Materials and Methods: We leveraged baseline data from the Adolescent Brain Cognitive Development (ABCD) study (n=9969; mean±standard deviation age=9.92±0.62 years; 47.1% female). Saliva samples were used for genotyping, and caregivers reported on their child's anxiety symptoms and trauma exposure. Fractional anisotropy (FA), a nonspecific measure of white matter integrity, was estimated for frontolimbic tracts. Results: Thirty-six percent of youth experienced one or more potentially traumatic events according to DSM-5 Criterion A (64% controls), and 45% were FAAH A-allele carriers (55% noncarriers). Relative to controls, trauma-exposed youth demonstrated higher anxiety and higher FA of the left uncinate. The FAAH A-allele (vs. CC) was associated with lower FA in the left fornix and left parahippocampal cingulum, and there was an indirect effect of FAAH genotype on anxiety through FA of the left fornix. Moreover, genotype moderated the association between FA of the left cingulum and anxiety. Conclusions: Our findings demonstrate distinct effects of trauma exposure and the FAAH C385A variant on frontolimbic pathways and subsequent anxiety risk in preadolescent children. This line of work may provide important insights into neurodevelopmental mechanisms leading to anxiety risk, and potential targets for intervention.

Neuroimaging Correlates of Post-Traumatic Stress Disorder in Traumatic Brain Injury: A Systematic Review of the Literature

IntroductionNeuroimaging has been a highly utilized technique for studying traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD) independently of one another, however, neuroimaging has increasingly been identified as a useful tool in better understanding TBI-related psychiatric conditions, such as PTSD.ObjectivesTo complete a systematic review of the literature examining neuroimaging findings in TBI-related PTSD and to highlight the current literature’s limitations in order to strengthen future research.MethodsA PRISMA compliant literature search was conducted in PubMed (MEDLINE), PsychINFO, EMBASE, and Scopus databases prior to May of 2019. The initial database query yielded 4388 unique articles, which were narrowed down based on specified inclusion criteria (e.g., clear TBI definition, clinician-diagnosed PTSD, statistically analyzed relationship between neuroimaging and PTSD, quantified time interval between TBI and neuroimaging).ResultsA final cohort of 10 articles met inclusion criteria, comprising the findings of 482 participants with TBI. Key neuroanatomical findings among the included articles suggest that PTSD is associated with significant changes in whole-brain networks of resting state connectivity and disruptions in bilateral frontal and temporal white matter tracts, fronto-limbic pathways, the internal capsule, and the uncinate fasciculus (Figure 1). Figure 1a:Neuroimaging Findings in TBI-related PTSD.Figure 1b.Replicated Neuroimaging Findings in TBI-related PTSD in the Right Uncinate Fasciculus.ConclusionsAdditional inquiry with attention to specified imaging timing post-injury, consistent TBI definitions, clinician-diagnosed TBI and PTSD, and control groups is crucial to extrapolating discrepancies between primary and TBI-related PTSD. Prospective studies could further differentiate predisposing factors from sequelae of TBI-related PTSD.DisclosureNo significant relationships.

P136. Trauma Exposure, Endocannabinoid Signaling, and Variation in Frontolimbic White Matter Pathways in Children

The endocannabinoid system plays a key role in modulating brain development throughout the lifespan, including myelination. Recent studies link a common variant (C385A) in the fatty acid amide hydrolase (FAAH) gene to higher endocannabinoid levels, lower anxiety, and altered frontolimbic development. Frontolimbic pathways demonstrate a protracted maturational course across childhood and adolescence, are associated with anxiety, and are sensitive to environmental stressors (e.g., trauma exposure).

Multimodal structural neuroimaging markers of risk and recovery from posttrauma anhedonia: A prospective investigation.

Anhedonic symptoms of posttraumatic stress disorder (PTSD) reflect deficits in reward processing that have significant functional consequences. Although recent evidence suggests that disrupted integrity of fronto-limbic circuitry is related to PTSD development, including anhedonic PTSD symptoms (posttrauma anhedonia [PTA]), little is known about potential structural biomarkers of long-term PTA as well as structural changes in fronto-limbic pathways associated with recovery from PTA over time. We investigated associations between white matter microstructure, gray matter volume, and PTA in 75 recently traumatized individuals, with a subset of participants (n = 35) completing follow-up assessment 12 months after trauma exposure. Deterministic tractography and voxel-based morphometry were used to assess changes in white and gray matter structure associated with changes in PTA. Reduced fractional anisotropy (FA) of the uncinate fasciculus at around the time of trauma predicted greater PTA at 12-months posttrauma. Further, increased FA of the fornix over time was associated with lower PTA between 1 and 12-months posttrauma. Increased gray matter volume of the ventromedial prefrontal cortex and precuneus over time was also associated with reduced PTA. The microstructure of the uncinate fasciculus, an amygdala-prefrontal white matter connection, may represent a biomarker of vulnerability for later PTA. Conversely, development and recovery from PTA appear to be facilitated by white and gray matter structural changes in a major hippocampal pathway, the fornix. The present findings shed new light on neuroanatomical substrates of recovery from PTA and characterize white matter biomarkers of risk for posttraumatic dysfunction.

White matter microstructure in youth with and at risk for bipolar disorder.

ObjectivesBipolar disorder (BD) and familial risk for BD have been associated with aberrant white matter (WM) microstructure in the corpus callosum and fronto‐limbic pathways. These abnormalities might constitute trait or state marker and have been suggested to result from aberrant maturation and to relate to difficulties in emotion regulation.MethodsTo determine whether WM alterations represent a trait, disease or resilience marker, we compared youth at risk for BD (n = 36 first‐degree relatives, REL) to youth with BD (n = 36) and healthy volunteers (n = 36, HV) using diffusion tensor imaging.ResultsIndividuals with BD and REL did not differ from each other in WM microstructure and, compared to HV, showed similar aberrations in the superior corona radiata (SCR)/corticospinal tract (CST) and the body of the corpus callosum. WM microstructure of the anterior CC showed reduced age‐related in‐creases in BD compared to REL and HV. Further, individuals with BD and REL showed in‐creased difficulties in emotion regulation, which were associated with the microstructure of the anterior thalamic radiation.DiscussionAlterations in the SCR/CST and the body of the corpus callosum appear to represent a trait marker of BD, whereas changes in other WM tracts seem to be a disease state marker. Our findings also support the role of aberrant developmental trajectories of WM microstructure in the risk architecture of BD, although longitudinal studies are needed to confirm this association. Finally, our findings show the relevance of WM microstructure for difficulties in emotion regulation—a core characteristic of BD.

Maternal Prenatal Stress Is Associated With Altered Uncinate Fasciculus Microstructure in Premature Neonates

BackgroundMaternal prenatal stress exposure (PNSE) increases risk for adverse psychiatric and behavioral outcomes in offspring. The biological basis for this elevated risk is poorly understood but may involve alterations to the neurodevelopmental trajectory of white matter tracts within the limbic system, particularly the uncinate fasciculus. Additionally, preterm birth is associated with both impaired white matter development and adverse developmental outcomes. In this study we hypothesized that higher maternal PNSE was associated with altered uncinate fasciculus microstructure in offspring. MethodsIn this study, 251 preterm infants (132 male, 119 female) (median gestational age = 30.29 weeks [range, 23.57–32.86 weeks]) underwent brain magnetic resonance imaging including diffusion-weighted imaging around term-equivalent age (median = 42.43 weeks [range, 37.86–45.71 weeks]). Measures of white matter microstructure were calculated for the uncinate fasciculus and the inferior longitudinal fasciculus, a control tract that we hypothesized was not associated with maternal PNSE. Multiple regressions were used to investigate the relationship among maternal trait anxiety scores, stressful life events, and white matter microstructure indices in the neonatal brain. ResultsAdjusting for gestational age at birth, postmenstrual age at scan, maternal age, socioeconomic status, sex, and number of days on parenteral nutrition, higher stressful life events scores were associated with higher axial diffusivity (β = .177, q = .007), radial diffusivity (β = .133, q = .026), and mean diffusivity (β = .149, q = .012) in the left uncinate fasciculus, and higher axial diffusivity (β = .142, q = .026) in the right uncinate fasciculus. ConclusionsThese findings suggest that PNSE is associated with altered development of specific frontolimbic pathways in preterm neonates as early as term-equivalent age.

Decreases in White Matter Integrity of Ventro-Limbic Pathway Linked to Post-Traumatic Stress Disorder in Mild Traumatic Brain Injury.

Post-traumatic stress disorder (PTSD) is commonly observed in military service members with mild traumatic brain injury (mTBI); however, the relationship between mTBI and PTSD is complex and not well understood. The present study aims to elucidate a link between the degree of alteration in limbic system-related white matter tracts and PTSD symptoms in an mTBI population. Diffusion-tensor imaging (DTI) with probabilistic tractography of the fronto-limbic pathways revealed decreased white matter integrity in the uncinate fasciculus in those with co-morbid mTBI and PTSD (n = 34), relative to those with only mTBI (n = 35). Additionally, fractional anisotropy (FA) and radial diffusivity (RD) measures in the bilateral uncinate fasciculus correlated with Post-Traumatic Stress Disorder Checklist Civilian version (PCL-C) scores, and primarily within the avoidance and re-experiencing domains. Findings from this study suggest the degree of traumatic injury within the limbic system could be directly related to post-traumatic stress and post-concussive symptoms, with disrupted white matter leading to significant PTSD outcomes.

Changes in laser-evoked potentials during hypnotic analgesia for chronic pain: a pilot study.

Hypnotic analgesia is one of the most effective nonpharmacological methods for pain control. Hypnosis and distraction of attention from pain might share similar mechanisms by which brain responses to painful stimulation could be similarly reduced in both states. There is ample evidence for the efficacy of clinical hypnosis as a psychological intervention in the treatment of acute or chronic pain. Results are conflicting, however, with some studies showing an increase, others a reduction, and others still no change in the amplitude of event-related brain potentials during hypnosis as compared to control conditions. Here we compared the effects of clinical hypnosis to simple distraction of attention during recording of laser-evoked potentials (LEPs) in patients with chronic pain. The dominant hand in ten patients with chronic pain was tested with LEPs during: (I) resting state; (II) clinical hypnosis, and (III) distraction of attention. Nociceptive responses elicited by LEPs were graded on a numerical rating scale (NRS), and the change in N2-P2 complex amplitude during the three experimental conditions was analyzed. N2-P2 amplitudes were significantly decreased during the hypnotic state as compared to the resting state and distraction of attention. Hypnosis is a modified state of consciousness that may differ from mental relaxation or distraction of attention from pain. A reduction in N2-P2 amplitude may result from the modulation of diverse brain networks, particularly the frontolimbic pathways, which could modify noxious stimuli input processing during hypnotic analgesia. Our findings indicate that several different brain mechanisms may act together in hypnosis and distraction of attention during pain processing and that clinical hypnosis may provide a useful non-invasive pain relief therapy.

Diffusion Tensor Imaging Tractography Reveals Disrupted White Matter Structural Connectivity Network in Healthy Adults with Insomnia Symptoms.

Neuroimaging studies have revealed that insomnia is characterized by aberrant neuronal connectivity in specific brain regions, but the topological disruptions in the white matter (WM) structural connectivity networks remain largely unknown in insomnia. The current study uses diffusion tensor imaging (DTI) tractography to construct the WM structural networks and graph theory analysis to detect alterations of the brain structural networks. The study participants comprised 30 healthy subjects with insomnia symptoms (IS) and 62 healthy subjects without IS. Both the two groups showed small-world properties regarding their WM structural connectivity networks. By contrast, increased local efficiency and decreased global efficiency were identified in the IS group, indicating an insomnia-related shift in topology away from regular networks. In addition, the IS group exhibited disrupted nodal topological characteristics in regions involving the fronto-limbic and the default-mode systems. To our knowledge, this is the first study to explore the topological organization of WM structural network connectivity in insomnia. More importantly, the dysfunctions of large-scale brain systems including the fronto-limbic pathways, salience network and default-mode network in insomnia were identified, which provides new insights into the insomnia connectome. Topology-based brain network analysis thus could be a potential biomarker for IS.

70. Laser-evoked potentials (LEPs) in chronic pain conditions during hypnotic analgesia

Hypnotic analgesia represents one of the most effective nonpharmacological methods for pain control. Hypnosis and distraction from pain might share similar mechanisms, implying that brain responses to painful stimulation should be similarly reduced in both situations. Literature data are conflicting, showing increase, reduction or no change in Event-Related Brain Potentials amplitudes during hypnosis compared to control conditions. Here we investigate effects of hypnosis and distraction during laser-evoked potentials (LEPs) in patients with chronic painful diseases. 9 patients with chronic pain were studied with LEPs on the dominant hand during resting state, medium and deep hypnosis (techniques for analgesia), and focused attention on article reading. Pain induced by LEPs was assessed with Numerical Rating Scale (NRS) and we analyzed N2/P2 complex amplitude change during the three conditions. Patients under hypnosis showed significant N2/P2 amplitudes decrease compared to resting state and distraction. Hypnosis is a physiological modified state of consciousness that may differ either from mental relaxation or distraction from pain. N2/P2 amplitude reduction may depend on different brain networks activation, in particular frontolimbic pathways, which could modify noxious stimuli input processing during hypnotic analgesia. Our results indicate that different brain mechanisms might act in hypnosis and distraction during pain processing.

Electroconvulsive therapy mediates neuroplasticity of white matter microstructure in major depression

Whether plasticity of white matter (WM) microstructure relates to therapeutic response in major depressive disorder (MDD) remains uncertain. We examined diffusion tensor imaging (DTI) correlates of WM structural connectivity in patients receiving electroconvulsive therapy (ECT), a rapidly acting treatment for severe MDD. Tract-Based Spatial Statistics (TBSS) applied to DTI data (61 directions, 2.5 mm3 voxel size) targeted voxel-level changes in fractional anisotropy (FA), and radial (RD), axial (AD) and mean diffusivity (MD) in major WM pathways in MDD patients (n=20, mean age: 41.15 years, 10.32 s.d.) scanned before ECT, after their second ECT and at transition to maintenance therapy. Comparisons made at baseline with demographically similar controls (n=28, mean age: 39.42 years, 12.20 s.d.) established effects of diagnosis. Controls were imaged twice to estimate scanning-related variance. Patients showed significant increases of FA in dorsal fronto-limbic circuits encompassing the anterior cingulum, forceps minor and left superior longitudinal fasciculus between baseline and transition to maintenance therapy (P<0.05, corrected). Decreases in RD and MD were observed in overlapping regions and the anterior thalamic radiation (P<0.05, corrected). Changes in DTI metrics associated with therapeutic response in tracts showing significant ECT effects differed between patients and controls. All measures remained stable across time in controls. Altered WM microstructure in pathways connecting frontal and limbic areas occur in MDD, are modulated by ECT and relate to therapeutic response. Increased FA together with decreased MD and RD, which trend towards normative values with treatment, suggest increased fiber integrity in dorsal fronto-limbic pathways involved in mood regulation.

Insula and Orbitofrontal Cortical Morphology in Substance Dependence Is Modulated by Sex

Frontolimbic circuits are involved in learning and decision-making processes thought to be affected in substance-dependent individuals. We investigated frontolimbic cortical morphometry in substance-dependent men and women and determined whether morphometric measurements correlated with decision-making performance. Twenty-eight abstinent SDI (17 men/11 women) were compared with 28 controls (13 men/15 women). Cortical thicknesses and volumes were computed by using FreeSurfer. After controlling for age and intracranial volume, group and sex effects were analyzed in 3 a priori regions of interest: the insula, orbitofrontal cortex, and anterior cingulate cortex by using analysis of covariance. A secondary whole-brain analysis was conducted to verify region-of-interest results and to explore potential differences in other brain regions. Region-of-interest analyses revealed a main effect of group on the left insula cortex, which was thinner in SDI compared with controls (P = .02). There was a group by sex interaction on bilateral insula volume (left, P = .02; right, P = .001) and right insula cortical thickness (P = .007). Compared with same-sex controls, female SDI had smaller insulae, whereas male SDI had larger insulae. Neither ACC nor OFC significantly differed across group. Performance on a decision-making task was better in controls than SDI and correlated with OFC measurements in the controls. SDI and controls differed in insula morphology, and those differences were modulated by sex. No group differences in OFC were observed, but OFC measurements correlated with negative-reinforcement learning in controls. These preliminary results are consistent with a hypothesis that frontolimbic pathways may be involved in behaviors related to substance dependence.

Elevated amygdala activity to negative faces in young adults with early onset major depressive disorder

Abnormalities in amygdala activity have been implicated in adolescents and older adults with major depressive disorder (MDD), but few studies have focused on young adults with early-onset MDD. In this study, we measured amygdala activity in 27 young adults with early-onset MDD and 25 healthy controls (HC) using functional magnetic resonance imaging (fMRI) with an emotional processing task. Both groups showed significant bilateral activation within the amygdala to threat-related facial expressions. In the matching face task, the activations of the left amygdala, thalamus, prefrontal and temporal cortex were significantly greater while the activation of the right prefrontal was significantly lower for the MDD group compared with the HC group. For the MDD group, there was a significant positive correlation between the activity of the amygdala and scores on the Chinese version of the Center for Epidemiologic Studies Depression Scale. Overall, our findings suggest that young adults with early-onset MDD may be characterized by abnormalities in nodes along the fronto-limbic pathways when facing threat-related facial expression.

Fronto-limbic dysfunction in borderline personality disorder: A 18F-FDG positron emission tomography study

IntroductionSeveral functional neuroimaging studies have demonstrated abnormalities in fronto-limbic pathways when comparing borderline personality disorder (BPD) patients with controls. The present study aimed to evaluate regional cerebral metabolism in euthymic BPD patients with similar measured impulsivity levels by means of 18F-FDG PET during resting state and to compare them against a control group. MethodsThe present study evaluates regional cerebral metabolism in 8 euthymic BPD patients with 18F-FDG PET during resting state as compared to 8 controls with similar socio-geographic characteristics. ResultsBPD patients presented a marked hypo-metabolism in frontal lobe and showed hyper-metabolism in motor cortex (paracentral lobules and post-central cortex), medial and anterior cingulus, occipital lobe, temporal pole, left superior parietal gyrus and right superior frontal gyrus. No significant differences appeared in basal ganglia or thalamus. ConclusionsResults reveal a dysfunction in patients' frontolimbic network during rest and provide further evidence for the importance of these regions in relation to BPD symptomatology.

Altered White Matter Microstructure in Children With Attention-Deficit/Hyperactivity Disorder

Identification of biomarkers is a priority for attention-deficit/hyperactivity disorder (ADHD). Studies have documented macrostructural brain alterations in ADHD, but few have examined white matter microstructure, particularly in preadolescent children. Given dramatic white matter maturation across childhood, microstructural differences seen in adolescents and adults with ADHD may reflect compensatory restructuring, rather than early neurophenotypic markers of the disorder. Using tract-based spatial statistics, mean fractional anisotropy (FA) maps were created using diffusion tensor imaging. FA, mean diffusivity (MD), and associated axial and radial diffusivities were compared between 16 children with ADHD and 20 healthy children (age 7-9 years). Youth with ADHD showed decreased FA in frontoparietal, frontolimbic, cerebellar, corona radiata, and temporo-occipital white matter compared with controls. In addition, ADHD was associated with lower MD in the posterior limb of the internal capsule and frontoparietal white matter and greater MD in frontolimbic white matter. Lower axial diffusion and/or higher radial diffusion were differentially observed for youth with ADHD in earlier versus later maturing areas of group FA/MD difference. This study suggests that, even prior to adolescence, ADHD represents a disorder of altered structural connectivity of the brain, characterized by distributed atypical white matter microstructure. In addition, later maturing frontolimbic pathways were abnormal in children with ADHD, likely due to delayed or decreased myelination, a finding not previously demonstrated in the adolescent or adult stages of the disorder. These results suggest that disruptions in white matter microstructure may play a key role in the early pathophysiology of ADHD.

Whole-brain voxel-based statistical analysis of gray matter and white matter in temporal lobe epilepsy

Volumetric MRI studies based on manual labeling of selected anatomical structures have provided in vivo evidence that brain abnormalities associated with temporal lobe epilepsy (TLE) extend beyond the hippocampus. Voxel-based morphometry (VBM) is a fully automated image analysis technique allowing identification of regional differences in gray matter (GM) and white matter (WM) between groups of subjects without a prior region of interest. The purpose of this study was to determine whole-brain GM and WM changes in TLE and to investigate the relationship between these abnormalities and clinical parameters. We studied 85 patients with pharmacologically intractable TLE and unilateral hippocampal atrophy and 47 age- and sex-matched healthy control subjects. The seizure focus was right sided in 40 patients and left sided in 45. Student's t test statistical maps of differences between patients' and controls' GM and WM concentrations were obtained using a general linear model. A further regression against duration of epilepsy, age of onset, presence of febrile convulsions, and secondary generalized seizures was performed with the TLE population. Voxel-based morphometry revealed that GM pathology in TLE extends beyond the hippocampus involving other limbic areas such as the cingulum and the thalamus, as well as extralimbic areas, particularly the frontal lobe. White matter reduction was found only ipsilateral to the seizure focus, including the temporopolar, entorhinal, and perirhinal areas. This pattern of structural changes is suggestive of disconnection involving preferentially frontolimbic pathways in patients with pharmacologically intractable TLE.

424. Executive function deficits in adults with attention deficit hyperactivity disorder (ADHD)

that S-ketamine and psilocybin produce overlapping psychotic symptoms in normal subjects that were associated with a common metabolic activation of prefrontal, limbic, striatal, and thalamic structures similarly as seen in some acute schizophrenic patients (Vollenweider 1998). In animals, behavioral effects of NMDA antagonists can be attenuated with the atypical 5-HT2A/D1,2,4 antagonist olanzapine or the 5-HT2A antagonist MDL 100907. This finding suggest that 1) 5-HT2 receptor antagonism may ameliorate ketamine-induced psychosis and 2) that serotonin via 5-HT2A receptors may modulate the glutamate system. To further explore the role of fronto-limbic pathways in acute psychotic states, the pretreatment effects of clozapine on S-ketamine and of ketanserin on psilocybin-induced metabolic hyperfrontality and associated symptoms were investigated in healthy volunteers in placebocontrolled studies using FDG-PET and statistical parametric mapping (SPM96). Drug-induced psychopathology was assessed after PET scanning using the Altered State of Consciousness Questionnaire. Pretreatment with the 5-HT2A/D2 antagonist clozapine (35 mg po) and the 5-HT2A antagonist ketanserin (50 mg), respectively, significantly reduced S-ketamineand psilocybin-induced metabolic hyperfrontality and associated psychotic symptoms. The present results strongly suggest that fronto-striato-thalamic pathways may be a common and critical substrate involved in both Sketamineand psilocybin-induced psychotic symptom formation. The finding that clozapine and ketanserin, respectively, significantly reduced S-ketamineand psilocybin-induced effects suggests that 5-HT2 receptor stimulation may be a common denominator in drug-induced and possibly also naturally occurring psychoses.

Psychosurgery and the limbic system.

SummaryThe limbic system can be considered to consist of a central ‘core’ from which three well-defined circuits emerge. These are the Papez or medial circuit, the basolateral circuit and the defence reaction circuit. The functions of the primitive limbic brain are modulated by a higher order control—the frontal lobe. Emotional responses and physiological changes have been obtained by stimulation of fronto-limbic pathways and limbic circuits and these have been used for location of target sites in psychosurgery. For the relief of intractable depression and anxiety, lesions are generally made in the lower medial quadrant or posteroorbital part of the frontal lobe, where there is a concentration of fronto-limbic connections. In primary obsessional neurosis lesions at this site produce less satisfactory results, but these illnesses may be helped by lesions in the cingulate gyrus, which is part of the Papez circuit. Patients with epilepsy and aggressive outbursts may respond to temporal lobotomy, or to operations, such as amygdalotomy, where lesions are placed in the defence reaction circuit.