Abnormalities in white matter tracts in the fronto-striatal-thalamic circuit are associated with verbal performance in 22q11.2DS.

BACKGROUND: Abnormalities in fronto-striatal-thalamic (FST) sub-circuits are present in schizophrenia and are associated with cognitive impairments. However, it remains unknown whether abnormalities in FST sub-circuits are present before psychosis onset. This may be elucidated by investigating 22q11.2 deletion syndrome (22q11DS), a genetic syndrome associated with a 30% risk for developing schizophrenia in adulthood and a decline in Verbal IQ (VIQ) preceding psychosis onset. Here, we examined white matter (WM) tracts in FST sub-circuits, especially those in the dorsolateral (DLPFC) and ventrolateral prefrontal cortex (VLPFC) sub-circuits, and their associations with VIQ in young adults with 22q11DS. METHODS: Diffusion MRI scans were acquired from 21 individuals with 22q11DS with prodromal symptoms of schizophrenia, 30 individuals with 22q11DS without prodromal symptoms, and 30 healthy controls (mean age: 21 ± 2 years). WM tracts were reconstructed between striatum and thalamus with rostral middle frontal gyrus (rMFG) and inferior frontal gyrus (IFG), representing DLPFC and VLPFC respectively. Fractional anisotropy (FA) and radial diffusivity (RD) were used for group comparisons. VIQ was assessed and associations with the diffusion measures were evaluated. RESULTS: FA was significantly increased and RD decreased in most tracts of the DLPFC and VLPFC sub-circuits in 22q11DS. Verbal IQ scores correlated negatively with FA and, at trend level, positively with RD in the right thalamus-IFG tract in 22q11DS with prodromal symptoms. CONCLUSIONS: While abnormalities in FST sub-circuits are associated with schizophrenia, we observed that these abnormalities are also present in 22q11DS individuals with prodromal symptoms and are associated with verbal performance in the right thalamus-IFG tract.

The influence of respiration on brainstem and cardiovagal response to auricular vagus nerve stimulation: A multimodal ultrahigh-field (7T) fMRI study.

BACKGROUND: Brainstem-focused mechanisms supporting transcutaneous auricular VNS (taVNS) effects are not well understood, particularly in humans. We employed ultrahigh field (7T) fMRI and evaluated the influence of respiratory phase for optimal targeting, applying our respiratory-gated auricular vagal afferent nerve stimulation (RAVANS) technique. HYPOTHESIS: We proposed that targeting of nucleus tractus solitarii (NTS) and cardiovagal modulation in response to taVNS stimuli would be enhanced when stimulation is delivered during a more receptive state, i.e. exhalation. METHODS: Brainstem fMRI response to auricular taVNS (cymba conchae) was assessed for stimulation delivered during exhalation (eRAVANS) or inhalation (iRAVANS), while exhalation-gated stimulation over the greater auricular nerve (GANctrl, i.e. earlobe) was included as control. Furthermore, we evaluated cardiovagal response to stimulation by calculating instantaneous HF-HRV from cardiac data recorded during fMRI. RESULTS: Our findings demonstrated that eRAVANS evoked fMRI signal increase in ipsilateral pontomedullary junction in a cluster including purported NTS. Brainstem response to GANctrl localized a partially-overlapping cluster, more ventrolateral, consistent with spinal trigeminal nucleus. A region-of-interest analysis also found eRAVANS activation in monoaminergic source nuclei including locus coeruleus (LC, noradrenergic) and both dorsal and median raphe (serotonergic) nuclei. Response to eRAVANS was significantly greater than iRAVANS for all nuclei, and greater than GANctrl in LC and raphe nuclei. Furthermore, eRAVANS, but not iRAVANS, enhanced cardiovagal modulation, confirming enhanced eRAVANS response on both central and peripheral neurophysiological levels. CONCLUSION: 7T fMRI localized brainstem response to taVNS, linked such response with autonomic outflow, and demonstrated that taVNS applied during exhalation enhanced NTS targeting.

Investigation into local white matter abnormality in emotional processing and sensorimotor areas using an automatically annotated fiber clustering in major depressive disorder.

This work presents an automatically annotated fiber cluster (AAFC) method to enable identification of anatomically meaningful white matter structures from the whole brain tractography. The proposed method consists of 1) a study-specific whole brain white matter parcellation using a well-established data-driven groupwise fiber clustering pipeline to segment tractography into multiple fiber clusters, and 2) a novel cluster annotation method to automatically assign an anatomical tract annotation to each fiber cluster by employing cortical parcellation information across multiple subjects. The novelty of the AAFC method is that it leverages group-wise information about the fiber clusters, including their fiber geometry and cortical terminations, to compute a tract anatomical label for each cluster in an automated fashion. We demonstrate the proposed AAFC method in an application of investigating white matter abnormality in emotional processing and sensorimotor areas in major depressive disorder (MDD). Seven tracts of interest related to emotional processing and sensorimotor functions are automatically identified using the proposed AAFC method as well as a comparable method that uses a cortical parcellation alone. Experimental results indicate that our proposed method is more consistent in identifying the tracts across subjects and across hemispheres in terms of the number of fibers. In addition, we perform a between-group statistical analysis in 31 MDD patients and 62 healthy subjects on the identified tracts using our AAFC method. We find statistical differences in diffusion measures in local regions within a fiber tract (e.g. 4 fiber clusters within the identified left hemisphere cingulum bundle (consisting of 14 clusters) are significantly different between the two groups), suggesting the ability of our method in identifying potential abnormality specific to subdivisions of a white matter structure.

Acupuncture modulates the abnormal brainstem activity in migraine without aura patients.

Migraine is a common neurological disease with a high prevalence and unsatisfactory treatment options. The specific pathophysiological mechanisms of migraine remain unclear, which restricts the development of effective treatments for this prevalent disorder. The aims of this study were to 1) compare the spontaneous brain activity differences between Migraine without Aura (MwoA) patients and healthy controls (HCs), using amplitude of low-frequency fluctuations (ALFF) calculation method, and 2) explore how an effective treatment (verum acupuncture) could modulate the ALFF of MwoA patients. One hundred MwoA patients and forty-six matched HCs were recruited. Patients were randomized to four weeks' verum acupuncture, sham acupuncture, and waiting list groups. Patients had resting state BOLD-fMRI scan before and after treatment, while HCs only had resting state BOLD-fMRI scan at baseline. Headache intensity, headache frequency, self-rating anxiety and self-rating depression were used for clinical efficacy evaluation. Compared with HCs, MwoA patients showed increased ALFF in posterior insula and putamen/caudate, and reduced ALFF in rostral ventromedial medulla (RVM)/trigeminocervical complex (TCC). After longitudinal verum acupuncture treatment, the decreased ALFF of the RVM/TCC was normalized in migraine patients. Verum acupuncture and sham acupuncture have different modulation effects on ALFF of RVM/TCC in migraine patients. Our results suggest that impairment of the homeostasis of the trigeminovascular nociceptive pathway is involved in the neural pathophysiology of migraines. Effective treatments, such as verum acupuncture, could help to restore this imbalance.

The altered right frontoparietal network functional connectivity in migraine and the modulation effect of treatment.

Aims This study aims to investigate the resting-state functional connectivity (rs-fc) of the right frontoparietal network (rFPN) between migraineurs and healthy controls (HCs) in order to determine how the rFPN rs-fc can be modulated by effective treatment. Methods One hundred patients and 46 matched HCs were recruited. Migraineurs were randomized to verum acupuncture, sham acupuncture, and waiting list groups. Resting-state functional magnetic resonance imaging data were collected before and after longitudinal treatments. Independent component analysis was applied in the data analysis. Results We found that migraineurs showed decreased rs-fc between the rFPN and bilateral precuneus compared with HCs. After treatments (real and sham), rFPN rs-fc with the precuneus was significantly reduced. This reduction was associated with headache intensity relief. In order to explore the role of the precuneus in acupuncture modulation, we performed a seed-based rs-fc analysis using the precuneus as a seed and found that the precuneus rs-fc with the bilateral rostral anterior cingulate cortex/medial prefrontal cortex, ventral striatum, and dorsolateral prefrontal cortex was significantly enhanced after treatment. Conclusion Our results suggest that migraineurs are associated with abnormal rFPN rs-fc. An effective treatment, such as acupuncture, may relieve symptoms by strengthening the cognitive adaptation/coping process. Elucidation of the adaptation/coping mechanisms may open up a new window for migraine management.

Thalamic Volume Is Reduced in Cervical and Laryngeal Dystonias.

BACKGROUND: Dystonia, a debilitating movement disorder characterized by abnormal fixed positions and/or twisting postures, is associated with dysfunction of motor control networks. While gross brain lesions can produce secondary dystonias, advanced neuroimaging techniques have been required to identify network abnormalities in primary dystonias. Prior neuroimaging studies have provided valuable insights into the pathophysiology of dystonia, but few directly assessed the gross volume of motor control regions, and to our knowledge, none identified abnormalities common to multiple types of idiopathic focal dystonia. METHODS: We used two gross volumetric segmentation techniques and one voxelwise volumetric technique (voxel based morphometry, VBM) to compare regional volume between matched healthy controls and patients with idiopathic primary focal dystonia (cervical, n = 17, laryngeal, n = 7). We used (1) automated gross volume measures of eight motor control regions using the FreeSurfer analysis package; (2) blinded, anatomist-supervised manual segmentation of the whole thalamus (also gross volume); and (3) voxel based morphometry, which measures local T1-weighted signal intensity and estimates gray matter density or volume at the level of single voxels, for both whole-brain and thalamus. RESULTS: Using both automated and manual gross volumetry, we found a significant volume decrease only in the thalamus in two focal dystonias. Decreases in whole-thalamic volume were independent of head and brain size, laterality of symptoms, and duration. VBM measures did not differ between dystonia and control groups in any motor control region. CONCLUSIONS: Reduced thalamic gross volume, detected in two independent analyses, suggests a common anatomical abnormality in cervical dystonia and spasmodic dysphonia. Defining the structural underpinnings of dystonia may require such complementary approaches.

Altered periaqueductal gray resting state functional connectivity in migraine and the modulation effect of treatment.

The aims of this study were to 1) compare resting state functional connectivity (rs-fc) of the periaqueductal gray (PAG), a key region in the descending pain modulatory system (DPMS) between migraine without aura (MwoA) patients and healthy controls (HC), and 2) investigate how an effective treatment can influence the PAG rs-fc in MwoA patients. One hundred MwoA patients and forty-six matched HC were recruited. Patients were randomized to verum acupuncture, sham acupuncture, and waiting list groups. Resting state fMRI data were collected and seed based functional connectivity analysis was applied. Compared with HC, MwoA patients showed reduced rs-fc between the PAG and rostral anterior cingulate cortex/medial prefrontal cortex (rACC/mPFC), key regions in the DPMS and other pain related brain regions. The reduced rs-fc between the PAG and rACC/mPFC was associated with increased migraine headache intensity at the baseline. After treatments, rs-fc between the PAG and the rACC in MwoA patients significantly increased. The changes of rs-fc among the PAG, rACC and ventral striatum were significantly associated with headache intensity improvement. Impairment of the DPMS is involved in the neural pathophysiology of migraines. Impaired DPMS in migraine patients can be normalized after effective treatment.

Multi-tensor investigation of orbitofrontal cortex tracts affected in subcaudate tractotomy.

Subcaudate tractotomy (SCT) is a neurosurgical lesioning procedure that can reduce symptoms in medically intractable obsessive compulsive disorder (OCD). Due to the putative importance of the orbitofrontal cortex (OFC) in symptomatology, fibers that connect the OFC, SCT lesion, and either the thalamus or brainstem were investigated with two-tensor tractography using an unscented Kalman filter approach. From this dataset, fibers were warped to Montreal Neurological Institute space, and probability maps with center-of-mass analysis were subsequently generated. In comparing fibers from the same OFC region, including medial OFC (mOFC), central OFC (cOFC), and lateral OFC (lOFC), the area of divergence for fibers connected with the thalamus versus the brainstem is posterior to the anterior commissure. At the anterior commissure, fibers connected with the thalamus run dorsal to those connected with the brainstem. As OFC fibers travel through the ventral aspect of the internal capsule, lOFC fibers are dorsal to cOFC and mOFC fibers. Using neuroanatomical comparison, tracts coursing between the OFC and thalamus are likely part of the anterior thalamic radiations, while those between the OFC and brainstem likely belong to the medial forebrain bundle. These data support the involvement of the OFC in OCD and may be relevant to creating differential lesional procedures of specific tracts or to developing deep brain stimulation programming paradigms.

Volumetric parcellation methodology of the human hypothalamus in neuroimaging: normative data and sex differences.

There is increasing evidence regarding the importance of the hypothalamus for understanding sex differences in relation to neurological, psychiatric, endocrine and sleep disorders. Although different in histology, physiology, connections and function, multiple hypothalamic nuclei subserve non-voluntary functions and are nodal points for the purpose of maintaining homeostasis of the organism. Thus, given the critical importance of hypothalamic nuclei and their key multiple roles in regulating basic functions, it is important to develop the ability to conduct in vivo human studies of anatomic structure, volume, connectivity, and function of hypothalamic regions represented at the level of its nuclei. The goals of the present study were to develop a novel method of semi-automated volumetric parcellation for the human hypothalamus that could be used to investigate clinical conditions using MRI and to demonstrate its applicability. The proposed new method subdivides the hypothalamus into five parcels based on visible anatomic landmarks associated with specific nuclear groupings and was confirmed using two ex vivo hypothalami that were imaged in a 7 T (7 T) scanner and processed histologically. Imaging results were compared with histology from the same brain. Further, the method was applied to 44 healthy adults (26 men; 18 women, comparable on age, handedness, ethnicity, SES) to derive normative volumes and assess sex differences in hypothalamic regions using 1.5 T MRI. Men compared to women had a significantly larger total hypothalamus, relative to cerebrum size, similar for both hemispheres, a difference that was primarily driven by the tuberal region, with the sex effect size being largest in the superior tuberal region and, to a lesser extent, inferior tuberal region. Given the critical role of hypothalamic nuclei in multiple chronic diseases and the importance of sex differences, we argue that the use of the novel methodology presented here will allow for critical investigations of these disorders and further delineation of potential treatments, particularly sex-specific approaches to gene and drug discoveries that involve hypothalamic nuclei.

Metabolic activity in the insular cortex and hypothalamus predicts hot flashes: an FDG-PET study.

CONTEXT: Hot flashes are a common side effect of adjuvant endocrine therapies (AET; leuprolide, tamoxifen, aromatase inhibitors) that reduce quality of life and treatment adherence in breast cancer patients. Because hot flashes affect only some women, preexisting neurobiological traits might predispose to their development. Previous studies have implicated the insula during the perception of hot flashes and the hypothalamus in thermoregulatory dysfunction. OBJECTIVE: The aim of the study was to understand whether neurobiological factors predict hot flashes. DESIGN: [18F]-Fluorodeoxyglucose (FDG) positron emission tomography (PET) brain scans coregistered with structural magnetic resonance imaging were used to determine whether metabolic activity in the insula and hypothalamic thermoregulatory and estrogen-feedback regions measured before and in response to AET predict hot flashes. Findings were correlated with CYP2D6 genotype because of CYP2D6 polymorphism associations with tamoxifen-induced hot flashes. OUTCOME MEASURES: We measured regional cerebral metabolic rate of glucose uptake (rCMRglu) in the insula and hypothalamus on FDG-PET. RESULTS: Of 18 women without hot flashes who began AET, new-onset hot flashes were reported by 10 (55.6%) and were detected objectively in nine (50%) participants. Prior to the use of all AET, rCMRglu in the insula (P ≤ 0.01) and hypothalamic thermoregulatory (P = 0.045) and estrogen-feedback (P = 0.007) regions was lower in women who reported developing hot flashes. In response to AET, rCMRglu was further reduced in the insula in women developing hot flashes (P ≤ 0.02). Insular and hypothalamic rCMRglu levels were lower in intermediate than extensive CYP2D6 metabolizers. CONCLUSIONS: Trait neurobiological characteristics predict hot flashes. Genetic variability in CYP2D6 may underlie the neurobiological predisposition to hot flashes induced by AET.

Food motivation circuitry hypoactivation related to hedonic and nonhedonic aspects of hunger and satiety in women with active anorexia nervosa and weight-restored women with anorexia nervosa.

BACKGROUND: Previous studies have provided evidence of food motivation circuitry dysfunction in individuals with anorexia nervosa. However, methodological limitations present challenges to the development of a cohesive neurobiological model of anorexia nervosa. Our goal was to investigate the neural circuitry of appetite dysregulation across states of hunger and satiety in active and weight-restored phases of anorexia nervosa using robust methodology to advance our understanding of potential neural circuitry abnormalities related to hedonic and nonhedonic state and trait. METHODS: We scanned women with active anorexia nervosa, weight-restored women with anorexia nervosa and healthy-weight controls on a 3-T Siemens magnetic resonance scanner while they viewed images of high- and low-calorie foods and objects before (premeal) and after (postmeal) eating a 400 kcal meal. RESULTS: We enrolled 12 women with active disease, 10 weight-restored women with anorexia nervosa and 11 controls in our study. Compared with controls, both weight-restored women and those with active disease demonstrated hypoactivity premeal in the hypothalamus, amygdala and anterior insula in response to high-calorie foods (v. objects). Postmeal, hypoactivation in the anterior insula persisted in women with active disease. Percent signal change in the anterior insula was positively correlated with food stimuli ratings and hedonic and nonhedonic appetite ratings in controls, but not women with active disease. LIMITATIONS: Our findings are limited by a relatively small sample size, which prevented the use of an analysis of variance model and exploration of interaction effects, although our substantial effect sizes of between-group differences suggest adequate power for our statistical analysis approach. Participants taking psychotropic medications were included. CONCLUSION: Our data provide evidence of potential state and trait hypoactivations in food motivation regions involved in the assessment of food's reward value and integration of these with interoceptive signalling of one's internal state of well-being, with important relations between brain activity and homeostatic and hedonic aspects of appetite. Our findings give novel evidence of disruption in neurobiological circuits and stress the importance of examining both state and trait characteristics in the investigation of brain phenotypes in individuals with anorexia nervosa.

Acupuncture mobilizes the brain's default mode and its anti-correlated network in healthy subjects.

Previous work has shown that acupuncture stimulation evokes deactivation of a limbic-paralimbic-neocortical network (LPNN) as well as activation of somatosensory brain regions. This study explores the activity and functional connectivity of these regions during acupuncture vs. tactile stimulation and vs. acupuncture associated with inadvertent sharp pain. Acupuncture during 201 scans and tactile stimulation during 74 scans for comparison at acupoints LI4, ST36 and LV3 was monitored with fMRI and psychophysical response in 48 healthy subjects. Clusters of deactivated regions in the medial prefrontal, medial parietal and medial temporal lobes as well as activated regions in the sensorimotor and a few paralimbic structures can be identified during acupuncture by general linear model analysis and seed-based cross correlation analysis. Importantly, these clusters showed virtual identity with the default mode network and the anti-correlated task-positive network in response to stimulation. In addition, the amygdala and hypothalamus, structures not routinely reported in the default mode literature, were frequently involved in acupuncture. When acupuncture induced sharp pain, the deactivation was attenuated or became activated instead. Tactile stimulation induced greater activation of the somatosensory regions but less extensive deactivation of the LPNN. These results indicate that the deactivation of the LPNN during acupuncture cannot be completely explained by the demand of attention that is commonly proposed in the default mode literature. Our results suggest that acupuncture mobilizes the anti-correlated functional networks of the brain to mediate its actions, and that the effect is dependent on the psychophysical response.

Time-variant fMRI activity in the brainstem and higher structures in response to acupuncture.

Acupuncture modulation of activity in the human brainstem is not well known. This structure is plagued by physiological artifact in neuroimaging experiments. In addition, most studies have used short (<15 min) block designs, which miss delayed responses following longer duration stimulation. We used brainstem-focused cardiac-gated fMRI and evaluated time-variant brain response to longer duration (>30 min) stimulation with verum (VA, electro-stimulation at acupoint ST-36) or sham point (SPA, non-acupoint electro-stimulation) acupuncture. Our results provide evidence that acupuncture modulates brainstem nuclei important to endogenous monoaminergic and opioidergic systems. Specifically, VA modulated activity in the substantia nigra (SN), nucleus raphe magnus, locus ceruleus, nucleus cuneiformis, and periaqueductal gray (PAG). Activation in the ventrolateral PAG was greater for VA compared to SPA. Linearly decreasing time-variant activation, suggesting classical habituation, was found in response to both VA and SPA in sensorimotor (SII, posterior insula, premotor cortex) brain regions. However, VA also produced linearly time-variant activity in limbic regions (amygdala, hippocampus, and SN), which was bimodal and not likely habituation--consisting of activation in early blocks, and deactivation by the end of the run. Thus, acupuncture induces different brain response early, compared to 20-30 min after stimulation. We attribute the fMRI differences between VA and SPA to more varied and stronger psychophysical response induced by VA. Our study demonstrates that acupuncture modulation of brainstem structures can be studied non-invasively in humans, allowing for comparison to animal studies. Our protocol also demonstrates a fMRI approach to study habituation and other time-variant phenomena over longer time durations.

MRI-based anatomical model of the human head for specific absorption rate mapping.

In this study, we present a magnetic resonance imaging (MRI)-based, high-resolution, numerical model of the head of a healthy human subject. In order to formulate the model, we performed quantitative volumetric segmentation on the human head, using T1-weighted MRI. The high spatial resolution used (1 x 1 x 1 mm(3)), allowed for the precise computation and visualization of a higher number of anatomical structures than provided by previous models. Furthermore, the high spatial resolution allowed us to study individual thin anatomical structures of clinical relevance not visible by the standard model currently adopted in computational bioelectromagnetics. When we computed the electromagnetic field and specific absorption rate (SAR) at 7 Tesla MRI using this high-resolution model, we were able to obtain a detailed visualization of such fine anatomical structures as the epidermis/dermis, bone structures, bone-marrow, white matter and nasal and eye structures.

Characterization of the "deqi" response in acupuncture.

BACKGROUND: Acupuncture stimulation elicits deqi, a composite of unique sensations that is essential for clinical efficacy according to traditional Chinese medicine (TCM). There is lack of adequate experimental data to indicate what sensations comprise deqi, their prevalence and intensity, their relationship to acupoints, how they compare with conventional somatosensory or noxious response. The objective of this study is to provide scientific evidence on these issues and to characterize the nature of the deqi phenomenon in terms of the prevalence of sensations as well as the uniqueness of the sensations underlying the deqi experience. METHODS: Manual acupuncture was performed at LI4, ST36 and LV3 on the extremities in randomized order during fMRI in 42 acupuncture naïve healthy adult volunteers. Non-invasive tactile stimulation was delivered to the acupoints by gentle tapping with a von Frey monofilament prior to acupuncture to serve as a sensory control. At the end of each procedure, the subject was asked if each of the sensations listed in a questionnaire or any other sensations occurred during stimulation, and if present to rate its intensity on a numerical scale of 1-10. Statistical analysis including paired t-test, analysis of variance, Spearman's correlation and Fisher's exact test were performed to compare responses between acupuncture and sensory stimulation. RESULTS: The deqi response was elicited in 71% of the acupuncture procedures compared with 24% for tactile stimulation when thresholded at a minimum total score of 3 for all the sensations. The frequency and intensity of individual sensations were significantly higher in acupuncture. Among the sensations typically associated with deqi, aching, soreness and pressure were most common, followed by tingling, numbness, dull pain, heaviness, warmth, fullness and coolness. Sharp pain of brief duration that occurred in occasional subjects was regarded as inadvertent noxious stimulation. The most significant differences in the deqi sensations between acupuncture and tactile stimulation control were observed with aching, soreness, pressure and dull pain. Consistent with its prominent role in TCM, LI4 showed the most prominent response, the largest number of sensations as well as the most marked difference in the frequency and intensity of aching, soreness and dull pain between acupuncture and tactile stimulation control. Interestingly, the dull pain generally preceded or occurred in the absence of sharp pain in contrast to reports in the pain literature. An approach to summarize a sensation profile, called the deqi composite, is proposed and applied to explain differences in deqi among acupoints. CONCLUSION: The complex pattern of sensations in the deqi response suggests involvement of a wide spectrum of myelinated and unmyelinated nerve fibers, particularly the slower conducting fibers in the tendinomuscular layers. The study provides scientific data on the characteristics of the 'deqi' response in acupuncture and its association with distinct nerve fibers. The findings are clinically relevant and consistent with modern concepts in neurophysiology. They can provide a foundation for future studies on the deqi phenomenon.

Hypothalamic abnormalities in schizophrenia: sex effects and genetic vulnerability.

BACKGROUND: This is a unique hypothalamic magnetic resonance imaging (MRI) study in schizophrenia, an important region in the limbic system. We hypothesized abnormal volumetric increases, with greater severity in multiplex families (more than one ill member) compared with simplex families (one ill). We tested the hypothesis that normal hypothalamic sexual dimorphism is disrupted in schizophrenia. METHODS: Eighty-eight DSM-III-R schizophrenia cases (40 simplex and 48 multiplex), 43 first-degree nonpsychotic relatives, and 48 normal comparisons systematically were compared. A 1.5-Tesla General Electric scanner was used to acquire structural MRI scans, and contiguous 3.1-mm slices were used to segment anterior and posterior hypothalamus. General linear model for correlated data and generalized estimating equations were used to compare cases, relatives, and controls on right and left hypothalamus, controlled for age, sex, and total cerebral volume. Spearman's correlations of hypothalamic volumes with anxiety were calculated to begin to examine arousal correlates with structural abnormalities. RESULTS: Findings demonstrated significantly increased hypothalamic volume in cases and nonpsychotic relatives, particularly in regions of paraventricular and mammillary body nuclei, respectively. This increase was linear from simplex to multiplex cases, was positively correlated with anxiety, and had a greater propensity in women. CONCLUSIONS: Findings suggest important implications for understanding genetic vulnerability of schizophrenia and the high rate of endocrine abnormalities.

Sex differences in prefrontal cortical brain activity during fMRI of auditory verbal working memory.

Functional imaging studies of sex effects in working memory (WMEM) are few, despite significant normal sex differences in brain regions implicated in WMEM. This functional MRI (fMRI) study tested for sex effects in an auditory verbal WMEM task in prefrontal, parietal, cingulate, and insula regions. Fourteen healthy, right-handed community subjects were comparable between the sexes, including on WMEM performance. Per statistical parametric mapping, women exhibited greater signal intensity changes in middle, inferior, and orbital prefrontal cortices than men (corrected for multiple comparisons). A test of mixed-sex groups, comparable on performance, showed no significant differences in the hypothesized regions, providing evidence for discriminant validity for significant sex differences. The findings suggest that combining men and women in fMRI studies of cognition may obscure or bias results.

The integrated response of the human cerebro-cerebellar and limbic systems to acupuncture stimulation at ST 36 as evidenced by fMRI.

Clinical and experimental data indicate that most acupuncture clinical results are mediated by the central nervous system, but the specific effects of acupuncture on the human brain remain unclear. Even less is known about its effects on the cerebellum. This fMRI study demonstrated that manual acupuncture at ST 36 (Stomach 36, Zusanli), a main acupoint on the leg, modulated neural activity at multiple levels of the cerebro-cerebellar and limbic systems. The pattern of hemodynamic response depended on the psychophysical response to needle manipulation. Acupuncture stimulation typically elicited a composite of sensations termed deqi that is related to clinical efficacy according to traditional Chinese medicine. The limbic and paralimbic structures of cortical and subcortical regions in the telencephalon, diencephalon, brainstem and cerebellum demonstrated a concerted attenuation of signal intensity when the subjects experienced deqi. When deqi was mixed with sharp pain, the hemodynamic response was mixed, showing a predominance of signal increases instead. Tactile stimulation as control also elicited a predominance of signal increase in a subset of these regions. The study provides preliminary evidence for an integrated response of the human cerebro-cerebellar and limbic systems to acupuncture stimulation at ST 36 that correlates with the psychophysical response.

Structural brain magnetic resonance imaging of limbic and thalamic volumes in pediatric bipolar disorder.

BACKGROUND: Youths with bipolar disorder are ideal for studying illness pathophysiology given their early presentation, lack of extended treatment, and high genetic loading. Adult bipolar disorder MRI studies have focused increasingly on limbic structures and the thalamus because of their role in mood and cognition. On the basis of adult studies, the authors hypothesized a priori that youths with bipolar disorder would have amygdalar, hippocampal, and thalamic volume abnormalities. METHOD: Forty-three youths 6-16 years of age with DSM-IV bipolar disorder (23 male, 20 female) and 20 healthy comparison subjects (12 male, eight female) similar in age and sex underwent structured and clinical interviews, neurological examination, and cognitive testing. Differences in limbic and thalamic brain volumes, on the logarithmic scale, were tested using a two-way (diagnosis and sex) univariate analysis of variance, with total cerebral volume and age controlled. RESULTS: The subjects with bipolar disorder had smaller hippocampal volumes. Further analysis revealed that this effect was driven predominantly by the female bipolar disorder subjects. In addition, both male and female youths with bipolar disorder had significantly smaller cerebral volumes. No significant hemispheric effects were seen. CONCLUSIONS: These findings support the hypothesis that the limbic system, in particular the hippocampus, may be involved in the pathophysiology of pediatric bipolar disorder. While this report may represent the largest MRI study of pediatric bipolar disorder to date, more work is needed to confirm these findings and to determine if they are unique to pediatric bipolar disorder.

Neurophysiology and neuroanatomy of pitch perception: auditory cortex.

We present original results and review literature from the past fifty years that address the role of primate auditory cortex in the following perceptual capacities: (1) the ability to perceive small differences between the pitches of two successive tones; (2) the ability to perceive the sign (i.e., direction) of the pitch difference [higher (+) vs. lower (-)]; and (3) the ability to abstract pitch constancy across changes in stimulus acoustics. Cortical mechanisms mediating pitch perception are discussed with respect to (1) gross and microanatomical distribution; and (2) candidate neural coding schemes. Observations by us and others suggest that (1) frequency-selective neurons in primary auditory cortex (A1) and surrounding fields play a critical role in fine-grained pitch discrimination at the perceptual level; (2) cortical mechanisms that detect pitch differences are neuroanatomically dissociable from those mediating pitch direction discrimination; (3) cortical mechanisms mediating perception of the "missing fundamental frequency (F0)" are neuroanatomically dissociable from those mediating pitch perception when F0 is present; (4) frequency-selective neurons in both right and left A1 contribute to pitch change detection and pitch direction discrimination; (5) frequency-selective neurons in right A1 are necessary for normal pitch direction discrimination; (6) simple codes for pitch that are based on single- and multiunit firing rates of frequency-selective neurons face both a "hyperacuity problem" and a "pitch constancy problem"-that is, frequency discrimination thresholds for pitch change direction and pitch direction discrimination are much smaller than neural tuning curves predict, and firing rate patterns change dramatically under conditions in which pitch percepts remain invariant; (7) cochleotopic organization of frequency-selective neurons bears little if any relevance to perceptual acuity and pitch constancy; and (8) simple temporal codes for pitch capable of accounting for pitches higher than a few hundred hertz have not been found in the auditory cortex. The cortical code for pitch is therefore not likely to be a function of simple rate profiles or synchronous temporal patterns. Studies motivated by interest in the neurophysiology and neuroanatomy of music perception have helped correct longstanding misconceptions about the functional role of auditory cortex in frequency discrimination and pitch perception. Advancing knowledge about the neural coding of pitch is of fundamental importance to the future design of neurobionic therapies for hearing loss.