Despite the proven effectiveness of selective serotonin reuptake inhibitors (SSRIs) and cognitive- behavioral therapy (CBT) in the treatment of obsessive- compulsive disorder (OCD , about half of patients show inadequate responses to the treatment strategies. For poor responders to SSRIs, in particular, additional pharmacologic treatment strategies such as combination drug treatment strategies have been investigated, and second- generation atypical antipsychotic drugs have been proven effective in the augmentation of SSRIs. However, even when these best available treatments are applied, a number of OCD patients remain severely affected and experience treatment - refractory OCD. Moreover, some research regarding long- term course and outcome of OCD patients has revealed that the probability of remission or partial remission still remains insufficient at the level of 40-60%, with substantial probabilities of relapse (15-48%). For such OCD patients, re- evaluation of clinical features along with ongoing treatments is needed to optimize the standard treatment strategies for OCD. Further devised and more intensive treatment strategies such as cognitive therapy or inpatient treatment may also be applied after re- evaluating psychopathological, neurobiological and environmental factors associated with the treatment- refractory in each individual. In addition, it seems important to determine the definition of “treatment- refractory” more distinctly and strictly for further application of more invasive options such as TMS or DBS.

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As the president of the World Society for Stereotactic and Functional Neurosurgery where majority of neurosurgeons performing operations for psychiatric disorders are involved, I introduce current consensus, issues to be solved, and situations of neurosurgery for psychiatric disorders (NPD in the world. WSSFN regards NPD as research stage treatment and it is not yet an established clinical practice. This means that there should be a strict well-designed protocol, IRB approval, audit and monitoring committees, and consent by the patient. These are the minimal requirement, and NPD must aim at treatment or relief of suffering in patients with psychiatric disorders. The difference between “clinical research” and “clinical practice” should be made clear to the patients, family, and the society. Deep brain stimulation (DBS) is the most preferred method of intervention, because this is less destructive, reversible, and well accepted as a treatment of intractable movement disorders. The most common subjects of NPD are intractable obsessive compulsive disorder (OCD) and treatment - resistant depression (TRD), while other conditions such as Alzheimer disease, anorexia, drug addiction and aggressiveness are investigated. There is, however, no unanimous agreement about the best location of deep brain stimulation in the brain. There are many targets of DBS proposed and investigated, and majority of them seem to be related with the medial forebrain bundle. Considering the intractability of severe OCD and TRD that are refractory to other treatments, the results of DBS for NPD seem promising and feasible to promote further large- scale studies. Japan alone can no longer be isolated from this field of neuroscience.

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Deep brain stimulation (DBS) has started from the therapy for intractable pain or involuntary movement, recognized as a therapy for cortico-striato-thalamo-cortical loop circuit in CNS, and has recently applied to some psychiatric disorders, such as treatment- refractory obsessive compulsive disorder (OCD) and depression. DBS therapy for intractable OCD obtained FDA approval in USA and CE mark approval in Europe. 94 DBS cases for intractable OCD have been reported. The average overall response rate is 64% (63.8±21.9%) . Three different target have mainly been reported. Case numbers (1) and the responded cases YBOCS less than 15 points (2), or 20 points (.) were as follows ; 1) anterior limb of internal capsule/ ventral striatum : 1. 42 cases, 2. 12 cases, 3. 15 cases, 2) nucleus accumbence ; 1. 33 cases, 2. 8-11 cases, 3. 13 cases, 3) subthalamic nucleus ; 1. 19 cases, 2. 7 cases, 3. 11 cases. We hope these DBS therapy for intractable OCD are recognized as a alternative adjuvant treatment for intractable OCD by Japanese psychiatrists, OCD patients and their families.

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Deep Brain Stimulation (DBS), a new therapy for refractory obsessive-compulsive disorder (OCD), has accumulating new evidence for its clinical efficacy in the world, except for Japan. In this paper, I’d like to describe the history of neurosurgical approach in clinical psychiatry field and the critical issues for its further introduction in this field.

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Understanding the pathophysiology of neuropsychiatric diseases and neural mechanism of functional recovery after brain/spinal cord injuries is important for development of effective therapeutic strategies against them. For such researches, primate model, which is akin to human regarding the structures of the body and central nervous system, is essential. The author has been using the macaque monkeys to study the neural mechanisms of functional recovery of dexterous hand movements after spinal cord injury and recovery of visually guided saccadic eye movements after lesion of the primary visual cortex and clarified the neural circuits responsible for the functional compensation after the injuries and plastic changes occurring in these circuits, and also the effects of modulatory factors such as “motivation”. Furthermore, we recently developed a new method of pathway- selective and reversible manipulation of particular pathway in the primate central nervous system and succeeded in causing the behavioral effects. Such technique may open up the possibility to develop the “path-way-targeted” therapy against the neuropsychiatric diseases and brain/spinal cord injuries.

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Transgenic mice have contributed immensely to biomedical science. However, the genetic and physiological differences between primates and mice, including their physiological functions, hamper the extrapolation of results from mouse disease models to direct clinical applications in humans. Thus, development of non- human primate models that mimic various human physiological functions, including the neuronal system, would accelerate the advance of biomedical research. In particular, genetically modified non- human primates would be a powerful human disease model for preclinical study of newly developed therapies, drugs, and basic science. The common marmoset (Callithrix jacchus) is an useful experimental animal in biomedical research fields such as neuroscience, stem cell research and regenerative medicine. We have produced transgenic marmosets using a self- inactivating lenti- viral vector. With the success of the transgenic marmoset, research into human disease, physiology, and the development of drug therapies is expected to increase. However, targeted gene knockout animals have not been produced by the lent- viral vector method. Production of targeted gene knockout and transgenic marmosets to introduce long DNA are the next problems to be solved in marmoset transgenesis research.

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The neocortex in mammals consists of neocortical areas, which are the regional differences that can be histochemically and morphologically distinguished (Brodmann, 1909). In order to understand the molecular mechanisms that form the areas and their functions in the adult neocortex, we have done a series of large scale screenings for the genes that are abundantly expressed in one of the representative areas (area 46, motor, TE and V1) and analyzed the detailed expression patterns. As the results, we have identified two groups of the genes that showed marked expression in the primary sensory area, particularly in V1, and association areas. The V1- selectively expression genes include OCC1/FSTL1, 5HT1B, 5HT2A, tetstican- 1, and - 2, while association area - selective genes include RBP4, PNMA5, SPARC, and SLITs. The V1 selective expression genes are to contribute to confer visual homeostasis under the dynamic change of the light amount. I speculate that the association area selective genes contribute to the enhancement of basal dendrites and spines of the pyramidal neurons in the association areas with several lines of evidence. The recent advance of gene technology in primates as presented in this particular issue of the journal will enable us to directly prove the function of these primate area- selective genes.

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By means of gene delivery with recombinant vectors based on adeno- associated virus (AAV ; serotypes 1 and 2), we developed a simian model of Parkinson disease through overexpression of α-synuclein that induces degeneration/loss of nigral dopamine neurons. Furthermore, we succeeded in protecting against the onset of Parkinson disease by gene delivery of parkin that is considered a functional molecule to reduce α-synuclein accumulation and suppress dopamine neuron death. In parkinsonian monkeys in which intranigral injections of an AAV vector expressing α-synuclein were made, another AAV vector expressing parkin was injected into the substantia nigra. More recently, we have developed a novel parkinsonian model that is subject to α-synuclein overexpression selective to the nigrostriatal dopamine pathway by applying gene manipulation with Cre- loxP site-specific recombination. First, a lentiviral vector pseudotyped with modified glycoprotein of rabies virus that expresses Cre recombinase was injected into the striatum. Then, intranigral injections of an AAV vector that has α-synuclein gene followed by the stop cassette flanked by the loxP sequence were made into the nigra. Then, we observed selective GFP expression in nigral dopamine neurons only on the side ipsilateral to the HIV- 1 and AAV vector injections. These primate models of Parkinson disease will be very useful for analyzing the pathophysiology of the disease and establishing strategies of gene therapy for the disease.

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[in Japanese]

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