A descriptive analysis of spontaneous reports of antipsychotic-induced tardive dyskinesia and other extrapyramidal symptoms in the Japanese Adverse Drug Event Report database.

AimThe aim of this study is to summarize the spontaneous reports of tardive dyskinesia (TD) and extrapyramidal symptoms (EPSs) that occurred in Japan over the past decade. MethodsThe study analyzed TD and EPS cases reported in the Japanese Adverse Drug Event Report database between April 2011 and March 2021. The cases were stratified by the diagnoses of schizophrenia, bipolar disorders, and depressive disorders. ResultsIn total, 800 patients including a total of 171 TD cases and 682 EPS cases were reported in the JADER database across psychiatric diagnosis. The cases were caused by first-generation antipsychotics (FGA, TD: n = 105, EPS: n = 245) and second-generation antipsychotics (SGA, TD: n = 144, EPS: n = 598). The SGA were categorized based on Neuroscience-based Nomenclature (NbN) regarding pharmacological domain and mode of action, which were reported evenly as the offending agents. Among reported treatment and outcome in TD cases (n = 67, 37.6%) and EPS cases (n = 405, 59.3%), the relatively limited number of TD cases were reported as recovered/improved was also limited (n = 32, 47.8%) compared to those of EPS cases (n = 266, 65.7%). Some cases still had residual symptoms or did not recover fully (TD: n = 21, 31.3%, EPS: n = 77, 19.0%). CONCLUSION: Tardive dyskinesia and EPS have been widely reported in Japan over the past decade across psychiatric diagnoses and antipsychotic classes. LIMITATIONS: It is important to acknowledge the presence of reporting bias and the lack of comparators to accurately assess risks. Owing to the nature of spontaneous reporting, the estimation of prevalence is not feasible.

Clinical benefit of second-generation long-acting injectable antipsychotics in preventing re-hospitalization in patients with schizophrenia: A real-world study in Japan.

BACKGROUND: Real-world evidence on the benefits of long-acting injectable (LAI) antipsychotics (AP) in patients with schizophrenia is limited, especially in the employed population in Japan. This study evaluates the effectiveness of LAI AP in preventing re-hospitalization in patients with schizophrenia, including the employed population. METHODS: This retrospective, observational, population-based study used the Japan Medical Data Center (JMDC) health insurance claims database to identify patients having schizophrenia before or on the day of the first LAI AP prescription (index date), and receiving LAI AP between April 1, 2012 and December 31, 2019. The number of all-cause, psychiatric-, and schizophrenia-related hospitalizations at baseline (365 days before index date) and during the 1-year follow-up period were evaluated. RESULTS: Of the 1692 patients who received LAI AP during the study period, 146 were included (employed: 55 [37.7 %]; dependent: 91 [62.3 %]). The mean age was 37 years; 50.7 % (n = 74) were females. During baseline period, 61 (41.8 %) patients were not hospitalized. During the follow-up period, 67 (45.9 %) patients underwent hospitalization ≤ 7 days; all-cause: 100 (68.7 %); psychiatry-related: 104 (76.2 %); schizophrenia-related: 114 (78.1 %). A higher proportion of patients were hospitalization-free during the follow-up in the employed vs. dependent population: all cause: 69.1 % vs. 61.5 %; psychiatric-related 76.4 % vs. 67.0 %, schizophrenia-related: 87.3 % vs. 71.4 %. CONCLUSION: This study demonstrated the effectiveness of LAI AP in preventing hospitalization in Japan. During the follow-up period, patients with schizophrenia receiving LAI AP, including the employed population, had a significant decrease in hospitalization length and re-hospitalization rate compared to baseline.

Time course of recovery of different motor functions following a reproducible cortical infarction in non-human primates.

A major challenge in human stroke research is interpatient variability in the extent of sensorimotor deficits and determining the time course of recovery following stroke. Although the relationship between the extent of the lesion and the degree of sensorimotor deficits is well established, the factors determining the speed of recovery remain uncertain. To test these experimentally, we created a cortical lesion over the motor cortex using a reproducible approach in four common marmosets, and characterized the time course of recovery by systematically applying several behavioral tests before and up to 8 weeks after creation of the lesion. Evaluation of in-cage behavior and reach-to-grasp movement revealed consistent motor impairments across the animals. In particular, performance in reaching and grasping movements continued to deteriorate until 4 weeks after creation of the lesion. We also found consistent time courses of recovery across animals for in-cage and grasping movements. For example, in all animals, the score for in-cage behaviors showed full recovery at 3 weeks after creation of the lesion, and the performance of grasping movement partially recovered from 4 to 8 weeks. In addition, we observed longer time courses of recovery for reaching movement, which may rely more on cortically initiated control in this species. These results suggest that different recovery speeds for each movement could be influenced by what extent the cortical control is required to properly execute each movement.

Impulsive and compulsive behaviors can be induced by opposite GABAergic dysfunctions inside the primate ventral pallidum.

Introduction: The ventral pallidum (VP) is central in the limbic Basal Ganglia circuit, controlling both appetitive (approach) and aversive (avoidance) motivated behaviors. Nevertheless, VP involvement in pathological aspects remains unclear, especially in the behavioral expression of different motivational dysfunctions. This study aimed to investigate how the VP contributes to the expression of abnormal behaviors via opposite GABAergic dysfunctions. Methods: Opposite GABAergic dysfunctions were induced by injecting muscimol (a GABAA agonist) and bicuculline (a GABAA antagonist) into monkeys. We determined the effects of both substances on self-initiated behaviors in lab-chair and in free-moving home-cage contexts in six monkeys, and in two animals performing an approach-avoidance task in appetitive and aversive contexts. Results: While the self-initiated behaviors induced by bicuculline injections in VP were characterized by compulsive behaviors such as repetitive grooming and self-biting, muscimol injections induced impulsive behaviors including limb movements in a lab-chair context and exploration behaviors in a free-moving context. More specific behavioral effects were observed in the approach-avoidance task. The muscimol injections induced premature responses and erroneous screen touches, which characterize impulsive and attention disorders, while the bicuculline injections into the VP increased passive avoidance (non-initiated action) and task-escape in an aversive context, suggesting an anxiety disorder. Conclusions: These results show that activating or blocking GABAergic transmission in the VP impairs motivated behaviors. Furthermore, the behavioral expressions produced by these opposite disturbances show that the VP could be involved in anxiety-driven compulsive disorders, such as OCD, as well as in impulsive disorders motivated by attention deficits or reward-seeking, as seen in ADHD or impulse control disorders.

Selective serotonin reuptake inhibitor treatment retunes emotional valence in primate ventral striatum.

Selective serotonin reuptake inhibitors (SSRIs) are widely used to treat psychiatric disorders with affective biases such as depression and anxiety. How SSRIs exert a beneficial action on emotions associated with life events is still unknown. Here we ask whether and how the effectiveness of the SSRI fluoxetine is underpinned by neural mechanisms in the ventral striatum. To address these issues, we studied the spiking activity of neurons in the ventral striatum of monkeys during an approach-avoidance task in which the valence assigned to sensory stimuli was manipulated. Neural responses to positive and negative events were measured before and during a 4-week treatment with fluoxetine. We conducted PET scans to confirm that fluoxetine binds within the ventral striatum at a therapeutic dose. In our monkeys, fluoxetine facilitated approach of rewards and avoidance of punishments. These beneficial effects were associated with changes in tonic and phasic activities of striatal neurons. Fluoxetine increased the spontaneous firing rate of striatal neurons and amplified the number of cells responding to rewards versus punishments, reflecting a drug-induced positive shift in the processing of emotionally valenced information. These findings reveal how SSRI treatment affects ventral striatum neurons encoding positive and negative valence and striatal signaling of emotional information. In addition to a key role in appetitive processing, our results shed light on the involvement of the ventral striatum in aversive processing. Together, the ventral striatum appears to play a central role in the action of SSRIs on emotion processing biases commonly observed in psychiatric disorders.

Ventral striatum supports Methylphenidate therapeutic effects on impulsive choices expressed in temporal discounting task.

Methylphenidate (MPH) is a dopamine transporter (DAT) inhibitor used to treat attention-deficit/hyperactivity-disorder (ADHD). ADHD patients make impulsive choices in delay discounting tasks (DDT) and MPH reduces such impulsivity, but its therapeutic site of action remains unknown. Based on the high density of DAT in the striatum, we hypothesized that the striatum, especially the ventral striatum (VS) and caudate nucleus which both encode temporal discounting, can be preferential MPH action sites. To determine whether one of these striatal territories is predominantly involved in the effect of MPH, we trained monkeys to make choices during DDT. First, consistent with clinical observations, we found an overall reduction of impulsive choices with a low dose of MPH administered via intramuscular injections, whereas we reported sedative-like effects with a higher dose. Then, using PET-imaging, we found that the therapeutic reduction of impulsive choices was associated with selective DAT occupancy of MPH in the VS. Finally, we confirmed the selective involvement of the VS in the effect of MPH by testing the animals' impulsivity with microinjections of the drug in distinct striatal territories. Together, these results show that the therapeutic effect of MPH on impulsive decisions is mainly restricted to its action in the VS.

The anterior caudate nucleus supports impulsive choices triggered by pramipexole.

BACKGROUND: Pramipexole is a dopamine agonist used as a treatment in PD and restless legs syndrome to reduce motor symptoms, but it often induces impulse control disorders. In particular, patients with impulse control disorders tend to make more impulsive choices in the delay discounting task, that is, they choose small immediate rewards over larger delayed ones more often than patients without impulse control disorders and healthy subjects do. Yet the site of action of pramipexole that produces these impulsive choices remains unknown. Based on the heterogeneity of corticostriatal projections and the massive dopamine innervation of the striatum, we hypothesized that impulsive choices triggered by dopamine treatments may be supported by a specific striatal territory. OBJECTIVES: This study aims to determine by which anteriorstriatum territory the Pramipexole trigger impulsive choices; the caudate nucleus, the ventral striatum or the putamen. METHODS: We compared pramipexole intramuscular injections to intracerebral microinjections within the three striatal territories in healthy monkeys trained to execute the delay discounting task, a behavioral paradigm typically used to evaluate impulsive choices. RESULTS: We found that pramipexole intramuscular injections induced impulsive choices in all monkeys. Local microinjections were performed inside the anterior caudate nucleus, ventral striatum, and anterior putamen and reproduced those impulsive choices when pramipexole was directly injected into the caudate nucleus, whereas injections into the ventral striatum or putamen had no effect on monkeys' choices. CONCLUSIONS: These results, consistent with clinical studies, suggest that impulsive choices triggered by pramipexole are supported by the caudate nucleus, allowing us to emphasize the importance of dopamine modulation inside this striatal territory in decision processes underlying impulsive behaviors. © 2019 International Parkinson and Movement Disorder Society.

Prior MDMA administration aggravates MPTP-induced Parkinsonism in macaque monkeys.

The aim of this study was to investigate the causal role of an early serotonin injury on parkinsonian-like motor symptomatology. Monkeys were pretreated with 3,4-methylenedioxy-N-methamphetamine (MDMA, or "ecstasy"), known to lesion serotonergic fibers, before being administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We combined behavioural assessment, PET imaging, and immunohistochemistry. Strikingly, prior MDMA administration aggravated MPTP-induced Parkinsonism and associated dopaminergic injury. Monkeys with early MDMA lesions developed parkinsonian deficits more rapidly and more severely. Interestingly, not all symptoms were impacted. Bradykinesia, rigidity and freezing were not affected by early MDMA lesions, whereas spontaneous activities, tremor and abnormal posture were significantly aggravated. Finally, as expected, MDMA induced a decrease of the serotonergic transporter availability. More surprisingly, we found that MDMA evoked also a decreased availability of the dopaminergic transporter to a lesser extent. Altogether, these results show that MDMA administration in non-human primates not only damage serotonergic terminals, but also injure dopaminergic neurons and enhance MPTP neurotoxic action, a completely new result in primates.

Disturbance of approach-avoidance behaviors in non-human primates by stimulation of the limbic territories of basal ganglia and anterior insula.

The basal ganglia (BG) are involved in motivation and goal-directed behavior. Recent studies suggest that limbic territories of BG not only support reward seeking (appetitive approach) but also the encoding of aversive conditioned stimuli (CS) and the production of aversive-related behaviors (avoidance or escape). This study aimed to identify inside two BG nuclei, the striatum and pallidum, the territories involved in aversive behaviors and to compare the effects of stimulating these territories to those resulting from stimulation of the anterior Insula (aIns), a region that is well-known to be involved in aversive encoding and associated behaviors. Two monkeys performed an approach/avoidance task in which they had to choose a behavior (approach or avoidance) in an appetitive (reward) or aversive (air-puff) context. During this task, either one (single-cue) or two (dual-cue) CS provided essential information about which context-adapted behavior should be selected. Microstimulation was applied during the CS presentation. Stimulation generally reduced approaches in the appetitive contexts and increased escape behaviors (premature responses) and/or passive avoidance (noninitiated action) in aversive context. These effects were more pronounced in ventral parts of all examined structures, with significant differences observed between stimulated structures. Thresholds to induce effects were lowest in the pallidum. Striatal stimulation led to the largest diversity of effects, with a subregion even leading to enhanced active avoidance. Finally, aIns stimulations produced stronger effects in the dual-cue context. These results provide causal evidence that limbic territories of BG, like aIns, play crucial roles in the selection of context-motivated behaviors.

Roles of Multiple Globus Pallidus Territories of Monkeys and Humans in Motivation, Cognition and Action: An Anatomical, Physiological and Pathophysiological Review.

The globus pallidus (GP) communicates with widespread cortical areas that support various functions, including motivation, cognition and action. Anatomical tract-tracing studies revealed that the anteroventral GP communicates with the medial prefrontal and orbitofrontal cortices, which are involved in motivational control; the anterodorsal GP communicates with the lateral prefrontal cortex, which is involved in cognitive control; and the posterior GP communicates with the frontal motor cortex, which is involved in action control. This organization suggests that distinct subdivisions within the GP play specific roles. Neurophysiological studies examining GP neurons in monkeys during behavior revealed that the types of information coding performed within these subdivisions differ greatly. The anteroventral GP is characterized by activities related to motivation, such as reward seeking and aversive avoidance; the anterodorsal GP is characterized by activity that reflects cognition, such as goal decision and action selection; and the posterior GP is characterized by activity associated with action preparation and execution. Pathophysiological studies have shown that GABA-related substances or GP lesions result in abnormal activity in the GP, which causes site-specific behavioral and motor symptoms. The present review article discusses the anatomical organization, physiology and pathophysiology of the three major GP territories in nonhuman primates and humans.

Ventral Pallidum Encodes Contextual Information and Controls Aversive Behaviors.

Successful avoidance of aversive outcomes is crucial for the survival of animals. Although accumulating evidence indicates that an indirect pathway in the basal ganglia is involved in aversive behavior, the ventral pallidum (VP), which is an important component of this pathway, has so far been implicated primarily in appetitive behavior. In this study, we used single-cell recordings and bicuculline (GABAA antagonist) injections to elucidate the role of VP both in the encoding of aversive context and in active avoidance. We found 2 populations of neurons that were preferentially activated by appetitive and aversive conditioned stimuli (CSs). In addition, VP showed appetitive and aversive outcome anticipatory activities. These activity patterns indicate that VP is involved in encoding and maintaining CS-induced aversive contextual information. Furthermore, the disturbance of VP activity by bicuculline injection increased the number of error trials in aversive trials. In particular, the subjects released the response bar prematurely, showed no response at all, or failed to avoid the aversive outcome. Overall, these results suggest that VP plays a central role in controlling CS-induced negative motivation to produce avoidance behavior.

Visuomotor signals for reaching movements in the rostro-dorsal sector of the monkey thalamic reticular nucleus.

The thalamic reticular nucleus (TRN) collects inputs from the cerebral cortex and thalamus and, in turn, sends inhibitory outputs to the thalamic relay nuclei. This unique connectivity suggests that the TRN plays a pivotal role in regulating information flow through the thalamus. Here, we analyzed the roles of TRN neurons in visually guided reaching movements. We first used retrograde transneuronal labeling with rabies virus, and showed that the rostro-dorsal sector of the TRN (TRNrd) projected disynaptically to the ventral premotor cortex (PMv). In other experiments, we recorded neurons from the TRNrd or PMv while monkeys performed a visuomotor task. We found that neurons in the TRNrd and PMv showed visual-, set-, and movement-related activity modulation. These results indicate that the TRNrd, as well as the PMv, is involved in the reception of visual signals and in the preparation and execution of reaching movements. The fraction of neurons that were non-selective for the location of visual signals or the direction of reaching movements was greater in the TRNrd than in the PMv. Furthermore, the fraction of neurons whose activity increased from the baseline was greater in the TRNrd than in the PMv. The timing of activity modulation of visual-related and movement-related neurons was similar in TRNrd and PMv neurons. Overall, our data suggest that TRNrd neurons provide motor thalamic nuclei with inhibitory inputs that are predominantly devoid of spatial selectivity, and that these signals modulate how these nuclei engage in both sensory processing and motor output during visually guided reaching behavior.

Representation of spatial- and object-specific behavioral goals in the dorsal globus pallidus of monkeys during reaching movement.

The dorsal aspect of the globus pallidus (GP) communicates with the prefrontal cortex and higher-order motor areas, indicating that it plays a role in goal-directed behavior. We examined the involvement of dorsal GP neurons in behavioral goal monitoring and maintenance, essential components of executive function. We trained two macaque monkeys to choose a reach target based on relative target position in a spatial goal task or a target shape in an object-goal task. The monkeys were trained to continue to choose a certain behavioral goal when reward volume was constant and to switch the goals when the volume began to decrease. Because the judgment for the next goal was made in the absence of visual signals, the monkeys were required to monitor and maintain the chosen goals during the reaching movement. We obtained three major findings. (1) GP neurons reflected more of the relative spatial position than the shape of the reaching target during the spatial goal task. During the object-goal task, the shape of the reaching object was represented more than the relative position. (2) The selectivity of individual neurons for the relative position was enhanced during the spatial goal task, whereas the object-shape selectivity was enhanced during the object-goal task. (3) When the monkeys switched the goals, the selectivity for either the position or shape also switched. Together, these findings suggest that the dorsal GP is involved in behavioral goal monitoring and maintenance during execution of goal-oriented actions, presumably in collaboration with the prefrontal cortex.

Development of multidimensional representations of task phases in the lateral prefrontal cortex.

The temporal structuring of multiple events is essential for the purposeful regulation of behavior. We investigated the role of the lateral prefrontal cortex (LPFC) in transforming external signals of multiple sensory modalities into information suitable for monitoring successive events across behavioral phases until an intended action is prompted and then initiated. We trained monkeys to receive a succession of 1 s visual, auditory, or tactile sensory signals separated by variable intervals and to then release a key as soon as the fourth signal appeared. Thus, the animals had to monitor and update information about the progress of the task upon receiving each signal preceding the key release in response to the fourth signal. We found that the initial, short-latency responses of LPFC neurons reflected primarily the sensory modality, rather than the phase or progress of the task. However, a task phase-selective response developed within 500 ms of signal reception, and information about the task phase was maintained throughout the presentation of successive cues. The task phase-selective activity was updated with the appearance of each cue until the planned action was initiated. The phase-selective activity of individual neurons reflected not merely a particular phase of the task but also multiple successive phases. Furthermore, we found combined representations of task phase and sensory modality in the activity of individual LPFC neurons. These properties suggest how information representing multiple phases of behavioral events develops in the LPFC to provide a basis for the temporal regulation of behavior.

[Neural mechanisms underlying the integration of perception and action].

The hallmark of higher-order brain functions is the ability to integrate and associate diverse sets of information in a flexible manner. Thus, fundamental knowledge about the mechanisms underlying of information in the brain can be obtained by examining the neural mechanisms involved in the generation of an appropriate motor command based on perceived sensory signals. In this review article, we have focused on the involvement of the neuronal networks centered at the lateral aspect of the frontal cortex in the process of motor selection and motor planning based on visual signals. We have initially discussed the role of the lateral prefrontal cortex in integrating multiple sets of visual signals to select a reach target and the participation of the premotor cortex in retrieving and integrating diverse sets of motor information, such as where should one reach out or which arm is to be used. Next, based on the results of the studies on ideomotor apraxia, we have hypothesized that there are at least 2 distinct levels of neural representation (virtual level and physical level). We have reviewed the evidence supporting the operation of 2 distinct classes of neuronal activities corresponding to these 2 levels. In conclusion, we propose that the frontal cortex initially processes information across sensory and motor domains at the virtual level to generate information about a forthcoming motor action (virtual action plan) and that this information is subsequently transformed into a motor command, such as muscle activity or movement direction, for an actual body movement at the physical level (physical motor plan). This proposed framework may be useful for explaining the diverse clinical conditions caused by brain lesions as well as for clarifying the neural mechanisms underlying the integration of perception and action.

Origins of multisynaptic projections from the basal ganglia to rostrocaudally distinct sectors of the dorsal premotor area in macaques.

We examined the organization of multisynaptic projections from the basal ganglia (BG) to the dorsal premotor area in macaques. After injection of the rabies virus into the rostral sector of the caudal aspect of the dorsal premotor area (F2r) and the caudal sector of the caudal aspect of the dorsal premotor area (F2c), second-order neuron labeling occurred in the internal segment of the globus pallidus (GPi) and the substantia nigra pars reticulata (SNr). Labeled GPi neurons were found in the caudoventral portion after F2c injection, and in the dorsal portion at the rostrocaudal middle level after F2r injection. In the SNr, F2c and F2r injections led to labeling in the caudal or rostral part, respectively. Subsequently, third-order neuron labeling was observed in the external segment of the globus pallidus (GPe), the subthalamic nucleus (STN), and the striatum. After F2c injection, labeled neurons were observed over a broad territory in the GPe, whereas after F2r injection, labeled neurons tended to be restricted to the rostral and dorsal portions. In the STN, F2c injection resulted in extensive labeling over the nucleus, whereas F2r injection resulted in labeling in the ventral portion only. After both F2r and F2c injections, labeled neurons in the striatum were widely observed in the striatal cell bridge region and neighboring areas, as well as in the ventral striatum. The present results revealed that the origins of multisynaptic projections to F2c and F2r in the BG are segregated in the output stations of the BG, whereas intermingling rather than segregation is evident with respect to their input station.