Intractable Psychiatric Disorders Research Articles

Interleukin-4 mitigates anxiety-like behavior and loss of neurons and fiber tracts in limbic structures in a microglial PPARγ-dependent manner after traumatic brain injury

Traumatic brain injury (TBI) is commonly followed by intractable psychiatric disorders and long-term changes in affect, such as anxiety. The present study sought to investigate the effect of repetitive intranasal delivery of interleukin-4 (IL-4) nanoparticles on affective symptoms after TBI in mice. Adult male C57BL/6 J mice (10–12 weeks of age) were subjected to controlled cortical impact (CCI) and assessed by a battery of neurobehavioral tests up to 35 days after CCI. Neuron numbers were counted in multiple limbic structures, and the integrity of limbic white matter tracts was evaluated using ex vivo diffusion tensor imaging (DTI). As STAT6 is a critical mediator of IL-4-specific transcriptional activation, STAT6 knockout mice were used to explore the role of endogenous IL-4/STAT6 signaling axis in TBI-induced affective disorders. We also employed microglia/macrophage (Mi/Mϕ)-specific PPARγ conditional knockout (mKO) mice to test if Mi/Mϕ PPARγ critically contributes to IL-4-afforded beneficial effects. We observed anxiety-like behaviors up to 35 days after CCI, and these measures were exacerbated in STAT6 KO mice but mitigated by repetitive IL-4 delivery. We discovered that IL-4 protected against neuronal loss in limbic structures, such as the hippocampus and the amygdala, and improved the structural integrity of fiber tracts connecting the hippocampus and amygdala. We also observed that IL-4 boosted a beneficial Mi/Mϕ phenotype (CD206+/Arginase 1+/PPARγ+ triple-positive) in the subacute injury phase, and that the numbers of Mi/Mϕ appositions with neurons were robustly correlated with long-term behavioral performances. Remarkably, PPARγ-mKO completely abolished IL-4-afforded protection. Thus, CCI induces long-term anxiety-like behaviors in mice, but these changes in affect can be attenuated by transnasal IL-4 delivery. IL-4 prevents the long-term loss of neuronal somata and fiber tracts in key limbic structures, perhaps due to a shift in Mi/Mϕ phenotype. Exogenous IL-4 therefore holds promise for future clinical management of mood disturbances following TBI.

A Longitudinal Magnetoencephalographic Study of the Effects of Deep Brain Stimulation on Neuronal Dynamics in Severe Anorexia Nervosa.

Anorexia Nervosa (AN) is a debilitating psychiatric disorder characterized by the relentless pursuit of thinness, leading to severe emaciation. Magnetoencephalography (MEG)was used to record the neuronal response in seven patients with treatment-resistant AN while completing a disorder-relevant food wanting task. The patients underwent a 15-month protocol, where MEG scans were conducted pre-operatively, post-operatively prior to deep brain stimulation (DBS) switch on, twice during a blind on/off month and at protocol end. Electrodes were implanted bilaterally into the nucleus accumbens with stimulation at the anterior limb of the internal capsule using rechargeable implantable pulse generators. Three patients met criteria as responders at 12 months of stimulation, showing reductions of eating disorder psychopathology of over 35%. An increase in alpha power, as well as evoked power at latencies typically associated with visual processing, working memory, and contextual integration was observed in ON compared to OFF sessions across all seven patients. Moreover, an increase in evoked power at P600-like latencies as well as an increase in γ-band phase-locking over anterior-to-posterior regions were observed for high- compared to low-calorie food image only in ON sessions. These findings indicate that DBS modulates neuronal process in regions far outside the stimulation target site and at latencies possibly reflecting task specific processing, thereby providing further evidence that deep brain stimulation can play a role in the treatment of otherwise intractable psychiatric disorders.

Electroconvulsive shock attenuated microgliosis and astrogliosis in the hippocampus and ameliorated schizophrenia-like behavior of Gunn rat

BackgroundAlthough electroconvulsive therapy (ECT) is regarded as one of the efficient treatments for intractable psychiatric disorders, the mechanism of therapeutic action remains unclear. Recently, many studies indicate that ECT affects the immune-related cells, such as microglia, astrocytes, and lymphocytes. Moreover, microglial activation and astrocytic activation have been implicated in the postmortem brains of schizophrenia patients. We previously demonstrated that Gunn rats showed schizophrenia-like behavior and microglial activation in their brains. The present study examined the effects of electroconvulsive shock (ECS), an animal counterpart of ECT, on schizophrenia-like behavior, microgliosis, and astrogliosis in the brain of Gunn rats.MethodsThe rats were divided into four groups, i.e., Wistar sham, Wistar ECS, Gunn sham, and Gunn ECS. ECS groups received ECS once daily for six consecutive days. Subsequently, prepulse inhibition (PPI) test was performed, and immunohistochemistry analysis was carried out to determine the activation degree of microglia and astrocytes in the hippocampus by using anti-CD11b and anti-glial fibrillary acidic protein (GFAP) antibody, respectively.ResultsWe found PPI deficit in Gunn rats compared to Wistar rats, and it was significantly improved by ECS. Immunohistochemistry analysis revealed that immunoreactivity of CD11b and GFAP was significantly increased in Gunn rats compared to Wistar rats. ECS significantly attenuated the immunoreactivity of both CD11b and GFAP in Gunn rats.ConclusionsECS ameliorated schizophrenia-like behavior of Gunn rats and attenuated microgliosis and astrogliosis in the hippocampus of Gunn rats. Accordingly, therapeutic effects of ECT may be exerted, at least in part, by inhibition of glial activation. These results may provide crucial information to elucidate the role of activated glia in the pathogenesis of schizophrenia and to determine whether future therapeutic interventions should attempt to up-regulate or down-regulate glial functions.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0688-2) contains supplementary material, which is available to authorized users.

Microarray Analysis of Human Blood During Electroconvulsive Therapy.

IntroductionElectroconvulsive therapy (ECT) is currently regarded as a significant treatment option for intractable psychiatric disorders, such as catatonic schizophrenia or treatment-resistant depression; however, the underlying molecular mechanism for its therapeutic effect remains obscure.MethodsEmploying microarray analysis (Human Genome U133 Plus 2.0 Array; Affymetrix, United States) of cDNA derived from the peripheral blood of patients with catatonic schizophrenia (n = 5), we detected a significant change in 145 genes (0.68%) before and after modified ECT (mECT). Moreover, we performed quantitative polymerase chain reaction validation of genes that had previously been suggested to be functionally related to schizophrenia.ResultsOf 4 genes examined (AKT3, TCF7, PPP3R1, and GADD45B), only TCF7 was increased during the mECT procedure (P = 0.0025).DiscussionThis study describes the first attempt to uncover the molecular mechanism of mECT using a microarray assay of mRNA derived from peripheral blood, and our results suggest that the TCF family may play a role in the functional mechanism of mECT.

Deep brain stimulation of the bilateral nucleus accumbens in normal rhesus monkey

The nucleus accumbens (NAc) has been considered as a novel target of deep brain stimulation (DBS) for intractable psychiatric disorders. Quite a few questions exist about this new treatment, and might be explored in nonhuman primate models. There are several reports on DBS of brain nucleus other than NAc in nonhuman primates. Therefore, we stereotactically implanted the electrodes into bilateral NAc under the guidance of MRI using a clinical Leksell stereotactic system in normal rhesus monkeys. NAc could be recognized as the area of continuity between the caudate nucleus and putamen in the coronal sections, which is beneath the internal capsule, and the gray matter nucleus between the ventromedial prefrontal cortex and anterior commissure in axial sections, which is medial to the putamen. NAc is mainly at a point 2.0-3.0 mm inferior, 3.0-4.0 mm anterior, and 4.5-5.5 mm lateral to the anterior commissure. The electrodes were implanted accurately and connected to an implantable pulse generator subcutaneously. After recovery from surgery, stimulation with a variety of parameters was trialed, and continuous stimulation at 90 μs, 3.5 V, 160, or 60 Hz was administered individually for 7 days. The behaviors and spontaneous locomotor activity of the animals did not change significantly during stimulation. This is the first report on DBS of NAc in nonhuman primates to the best of our knowledge. Bilateral electrical stimulation of NAc is a safe treatment. This model could be helpful in further studies on the clinical use of NAc stimulation for psychiatric disorders and for a better understanding of the functions of this nucleus.

The Elements of Style: A Tribute to Suzanne Corkin

When Brad Postle invited me to submit a contribution to this Festschrift for Sue Corkin, I had to mull over what to present. I knew there would be many scientific papers but wanted to do something more personal. What I decided might be meaningful to Sue would be a contribution about her role in the development of women scientists in her lab. I know she was very important to me in this respect. I started with all the women I could think of who had been in Sueʼs lab around my time, contacted them, and asked them to help me find others, especially those who came before and after me. Those who responded are included here. There are 20 women representing many different roles in Sueʼs lab: research scientist, undergraduate student, graduate student, postdoctoral fellow, secretary, research assistant. Their dates and roles in the lab and what they are doing now are presented in Table 1. To provide a little structure but not to constrain their responses too much, I provided some intentionally vague guiding questions and left it up to them as to which ones they wanted to address. My edits have been confined to explaining abbreviations and special terms [in brackets], shortening some responses without changing the meaning (I hope), and offering some grammatical improvements that I believe Sue would have done herself if sheʼd been given the opportunity. Though my name is here as author, I can properly take credit for only one twentieth of the content of this article. I am indebted to these many women who took the time to reminisce in a public forum—the “public” part may not seem extraordinary until you get to the final entry! Needless to say, we are all tremendously indebted to Sue herself, in both predictable and surprising ways. We hope you enjoy the reconstruction of life in the Corkin lab over the years and its reverberations in our lives to the present day.

Deep Brain Stimulation in Parkinsonian Patients—Implications for Trialing DBS in Intractable Psychiatric Disorders

Deep Brain Stimulation in Parkinsonian Patients—Implications for Trialing DBS in Intractable Psychiatric Disorders

Personal Memories of the History of Stereotactic Neurosurgery

This article summarizes the author's personal memories of the first 50 years of stereotactic neurosurgery. The author provides a short summary of his education and his introduction to stereotactic neurosurgery. Some great pioneers of the field who played an important role in his training, including John F. Gillingham, Jean Talairach, Guillaume Guiot, Edvard Kandel, Hirotaro Narabayashi, Irving Cooper, Henry Wycis, and Lars Leksell, are described in detail. The author then discusses his own work in the treatment of movement disorders, chronic pain, epilepsy, and intractable psychiatric disorders. For his contributions to the field, the author received the Spiegel-Wycis Medal of the World Society for Stereotactic and Functional Neurosurgery in 2001.

Improvement in Severe Self-Mutilation Following Limbic Leucotomy

The efficacy of neurosurgical intervention for self-mutilation behavior associated with severe, intractable psychiatric disorders remains undetermined. We report the effects of limbic leucotomy in 5 consecutive patients with severe self-mutilation behaviors. After unsolicited referrals from their psychiatrists and careful consideration by the Massachusetts General Hospital Cingulotomy Assessment Committee (MGH-CAC), 5 patients were treated with limbic leucotomy. Their primary DSM-IV psychiatric diagnoses were either obsessive-compulsive disorder or schizoaffective disorder. Comorbid severe, treatment-refractory self-mutilation was an additional target symptom. Outcome was measured by an independent observer using the Clinical Global Improvement. Current Global Psychiatric-Social Status Rating, and DSM-IV Global Assessment of Functioning scales in addition to telephone interviews with patients, families, their psychiatrists, and treatment teams. The mean postoperative follow-up period was 31.5 months. All measures indicated sustained improvement in 4 of 5 patients. In particular, there was a substantial decrease in self-mutilation behaviors. Postoperative complications were transient in nature. and postoperative compared with preoperative neuropsychological assessments revealed no clinically significant deficits. In carefully selected patients as described in this report, limbic leucotomy may be an appropriate therapeutic consideration for self-mutilation associated with severe, intractable psychiatric disorders.

Contemporary psychosurgery and a look to the future

Despite a long and controversial history, psychosurgery has persisted as a modern treatment option for some severe, medically intractable psychiatric disorders. The goal of this study was to review the current state of psychosurgery. In this review, the definition of psychosurgery, patient selection criteria, and anatomical and physiological rationales for cingulotomy, subcaudate tractotomy, anterior capsulotomy, and limbic leukotomy are discussed. The historical developments, modern procedures, and results of these four contemporary psychosurgical procedures are also reviewed. Examples of recent advances in neuroscience indicating a future role for neurosurgical intervention for psychiatric disease are also mentioned. A thorough understanding of contemporary psychosurgery will help neurosurgeons and other physicians face the ethical, social, and technical challenges that are sure to lie ahead as modern science continues to unlock the secrets of the mind and brain.

A cohort study of psychosurgery cases from a defined population.

All cases from an urban population treated by psychosurgery over a 20 year period were followed up; 44 out of 47 were available for study, and 33 of these were interviewed. Outcome was measured on a five-point scale, and follow-up was from 1 to 20 years, with a mean of 11; almost all patients previously had had severe, disabling and intractable illnesses. Operations were non-stereotactic (36), stereotactic (6), with double procedures in one case: outcome was better in the non-stereotactic group. On a five-point scale of outcome, 25 of the 33 interviewed patients were placed in the two best categories, as were eight patients of the 11 who were assessed by case records. Adverse effects were reported in 14 cases, but most were not serious. Only one death could definitely be related to operation. Depression, agoraphobia, obsessional neurosis, and certain aspects of schizophrenia all responded well in the majority of cases. Leucotomy should remain available as a treatment of last resort for some intractable psychiatric disorders.

Anterior cerebellar vermal stimulation: Effect on behavior and basal forebrain neurochemistry in rat

Stimulation of the anterior cerebellar vermis (ACV) has been shown to be of therapeutic value in several patients with chronic intractable psychiatric disorders, although the mechanism of action of ACV stimulation remains obscure. The present study sought to clarify how cerebellar stimulation might function by investigating the behavioral and biochemical effects of ACV stimulation in rats. Stimulation was found to increase the amplitude of the acoustic startle response and to produce a borderline enhancement of the potentiated startle effect, results that were interpreted as evidence that ACV stimulation enhances responsiveness to significant environmental cues. A concurrent increase in dopamine turnover and a decrease in serotonin release in the nucleus accumbens suggest possible mechanisms of action of the stimulation. It is proposed that cerebellar stimulation may exert a positive therapeutic effect only in Type II schizophrenia (negative symptomatology), a category of cases possibly associated with an underactive mesolimbic dopamine pathway and, hence, not responsive to neuroleptic treatment.

Editorial: Psychosurgery--justifiable?

Today, in spite of the public agitation and rhetorical violence — as well as the amount of attention and time given to the subject of psychosurgery — the protedure is uncommon in this country. Not a single psychosurgical procedure was carried out last year for patients with severe mental illness in the hospitals under the direction of the New York State Department of Mental Hygiene, the largest mental-hospital system in the country, if not the world. Yet some procedures are done —usually in the university medical centers — for those referred for presumably intractable psychiatric disorders, for recurrent episodes of . . .