Timothy Spellman

Repeated Cortico-Striatal Stimulation Generates Persistent OCD-Like Behavior

What Causes Obsessive Compulsive Disorder? Obsessive compulsive disorder is a severe, chronic mental illness that affects millions of individuals. However, the mechanisms underlying this disease are still largely unknown (see the Perspective by Rauch and Carlezon Jr.). Ahmari et al. (p. 1234) stimulated glutamatergic pathways between the orbitofrontal cortex and the ventromedial striatum and used grooming to assess obsessive compulsive behavior in mice. Repetitive stimulation over days triggered changes in the neuronal responses of the ventromedial striatum. Over time, the behavior of the animals became independent of stimulation and could be prevented by the antidepressant fluoxetine. Burguière et al. (p. 1243) investigated the neural basis of obsessive compulsive symptoms in a mutant mouse that showed excessive expression of a conditioned form of grooming. Hyperactivation of projections from the orbitofrontal cortex to the striatum increases repetitive grooming in mice. [Also see Perspective by Rauch and Carlezon] Although cortico-striato-thalamo-cortical (CSTC) circuit dysregulation is correlated with obsessive compulsive disorder (OCD), causation cannot be tested in humans. We used optogenetics in mice to simulate CSTC hyperactivation observed in OCD patients. Whereas acute orbitofrontal cortex (OFC)–ventromedial striatum (VMS) stimulation did not produce repetitive behaviors, repeated hyperactivation over multiple days generated a progressive increase in grooming, a mouse behavior related to OCD. Increased grooming persisted for 2 weeks after stimulation cessation. The grooming increase was temporally coupled with a progressive increase in light-evoked firing of postsynaptic VMS cells. Both increased grooming and evoked firing were reversed by chronic fluoxetine, a first-line OCD treatment. Brief but repeated episodes of abnormal circuit activity may thus set the stage for the development of persistent psychopathology.

Hippocampal-prefrontal input supports spatial encoding in working memory

Spatial working memory, the caching of behaviourally relevant spatial cues on a timescale of seconds, is a fundamental constituent of cognition. Although the prefrontal cortex and hippocampus are known to contribute jointly to successful spatial working memory, the anatomical pathway and temporal window for the interaction of these structures critical to spatial working memory has not yet been established. Here we find that direct hippocampal–prefrontal afferents are critical for encoding, but not for maintenance or retrieval, of spatial cues in mice. These cues are represented by the activity of individual prefrontal units in a manner that is dependent on hippocampal input only during the cue-encoding phase of a spatial working memory task. Successful encoding of these cues appears to be mediated by gamma-frequency synchrony between the two structures. These findings indicate a critical role for the direct hippocampal–prefrontal afferent pathway in the continuous updating of task-related spatial information during spatial working memory.

Thalamic projections sustain prefrontal activity during working memory maintenance

The mediodorsal thalamus (MD) shares reciprocal connectivity with the prefrontal cortex (PFC), and decreased MD–PFC connectivity is observed in schizophrenia patients. Patients also display cognitive deficits including impairments in working memory, but a mechanistic link between thalamo–prefrontal circuit function and working memory is missing. Using pathway-specific inhibition, we found directional interactions between mouse MD and medial PFC (mPFC), with MD-to-mPFC supporting working memory maintenance and mPFC-to-MD supporting subsequent choice. We further identify mPFC neurons that display elevated spiking during the delay, a feature that was absent on error trials and required MD inputs for sustained maintenance. Strikingly, delay-tuned neurons had minimal overlap with spatially tuned neurons, and each mPFC population exhibited mutually exclusive dependence on MD and hippocampal inputs. These findings indicate a role for MD in sustaining prefrontal activity during working memory maintenance. Consistent with this idea, we found that enhancing MD excitability was sufficient to enhance task performance.

Molecular Substrates of Altered Axonal Growth and Brain Connectivity in a Mouse Model of Schizophrenia

22q11.2 deletion carriers show specific cognitive deficits, and ∼30% of them develop schizophrenia. One of the disrupted genes is ZDHHC8, which encodes for a palmitoyltransferase. We show that Zdhhc8-deficient mice have reduced palmitoylation of proteins that regulate axonal growth and branching. Analysis of axonal projections of pyramidal neurons from both Zdhhc8-deficient and Df(16)A(+/-) mice, which model the 22q11.2 deletion, revealed deficits in axonal growth and terminal arborization, which can be prevented by reintroduction of active ZDHHC8 protein. Impaired terminal arborization is accompanied by a reduction in the strength of synaptic connections and altered functional connectivity and working memory. The effect of ZDHHC8 is mediated in part via Cdc42-dependent modulation of Akt/Gsk3β signaling at the tip of the axon and can be reversed by pharmacologically decreasing Gsk3β activity during postnatal brain development. Our findings provide valuable mechanistic insights into the cognitive and psychiatric symptoms associated with a schizophrenia-predisposing mutation.

Direct Ventral Hippocampal-Prefrontal Input Is Required for Anxiety-Related Neural Activity and Behavior

The ventral hippocampus (vHPC), medial prefrontal cortex (mPFC), and basolateral amygdala (BLA) are each required for the expression of anxiety-like behavior. Yet the role of each individual element of the circuit is unclear. The projection from the vHPC to the mPFC has been implicated in anxiety-related neural synchrony and spatial representations of aversion. The role of this projection was examined using multi-site neural recordings combined with optogenetic terminal inhibition. Inhibition of vHPC input to the mPFC disrupted anxiety and mPFC representations of aversion, and reduced theta synchrony in a pathway-, frequency- and task-specific manner. Moreover, bilateral, but not unilateral, inhibition altered physiological correlates of anxiety in the BLA, mimicking a safety-like state. These results reveal a specific role for the vHPC-mPFC projection in anxiety-related behavior and the spatial representation of aversive information within the mPFC.

Differential effects of high-dose magnetic seizure therapy and electroconvulsive shock on cognitive function.

BACKGROUND Magnetic seizure therapy (MST) is under investigation as an alternative form of convulsive therapy that induces more focal seizures and spares cortical regions involved in memory. With a newly expanded version of the Columbia University Primate Cognitive Profile, we compared the cognitive effects of high-dose MST delivered at 100 Hz (6 x seizure threshold) with electroconvulsive shock (ECS) delivered at 2.5 x seizure threshold. METHODS Daily high-dose MST, ECS, and sham (anesthesia-only) were administered for 4 weeks each in a within-subject crossover design. Rhesus macaques (n = 3) were trained on five cognitive tasks assessing automatic memory, anterograde learning and memory, combined anterograde and retrograde simultaneous chaining, and spatial and serial working memory. Acutely after each intervention, monkeys were tested on the cognitive battery twice daily, separated by a 3-hour retention interval. RESULTS Subjects were slower to complete criterion tasks (p values < .0001) after ECS, compared with sham and high-dose MST. Moreover, time to task-completion after high-dose MST did not differ from sham. Of six measures of accuracy, treatment effects were found in four; in all of these, ECS but not MST fared worse than sham. On all accuracy and time to completion measurements, subjects performed as well after high-dose MST as subjects from a previous study on moderate-dose MST. CONCLUSIONS These findings provide evidence that high-dose MST results in benign acute cognitive side-effect profile relative to ECS and are in line with our previous studies.

Focal Electrically Administered Seizure Therapy: A Novel form of ECT Illustrates the Roles of Current Directionality, Polarity, and Electrode Configuration in Seizure Induction

Electroconvulsive therapy (ECT) is a mainstay in the treatment of severe, medication-resistant depression. The antidepressant efficacy and cognitive side effects of ECT are influenced by the position of the electrodes on the head and by the degree to which the electrical stimulus exceeds the threshold for seizure induction. However, surprisingly little is known about the effects of other key electrical parameters such as current directionality, polarity, and electrode configuration. Understanding these relationships may inform the optimization of therapeutic interventions to improve their risk/benefit ratio. To elucidate these relationships, we evaluated a novel form of ECT (focal electrically administered seizure therapy, FEAST) that combines unidirectional stimulation, control of polarity, and an asymmetrical electrode configuration, and contrasted it with conventional ECT in a nonhuman primate model. Rhesus monkeys had their seizure thresholds determined on separate days with ECT conditions that crossed the factors of current directionality (unidirectional or bidirectional), electrode configuration (standard bilateral or FEAST (small anterior and large posterior electrode)), and polarity (assignment of anode and cathode in unidirectional stimulation). Ictal expression and post-ictal suppression were quantified through scalp EEG. Findings were replicated and extended in a second experiment with the same subjects. Seizures were induced in each of the 75 trials, including 42 FEAST procedures. Seizure thresholds were lower with unidirectional than with bidirectional stimulation (p<0.0001), and lower in FEAST than in bilateral ECS (p=0.0294). Ictal power was greatest in posterior-anode unidirectional FEAST, and post-ictal suppression was strongest in anterior-anode FEAST (p=0.0008 and p=0.0024, respectively). EEG power was higher in the stimulated hemisphere in posterior-anode FEAST (p=0.0246), consistent with the anode being the site of strongest activation. These findings suggest that current directionality, polarity, and electrode configuration influence the efficiency of seizure induction with ECT. Unidirectional stimulation and novel electrode configurations such as FEAST are two approaches to lowering seizure threshold. Furthermore, the impact of FEAST on ictal and post-ictal expression appeared to be polarity dependent. Future studies may examine whether these differences in seizure threshold and expression have clinical significance for patients receiving ECT.

Synchrony in schizophrenia: a window into circuit-level pathophysiology

As a complex neuropsychiatric disease with both hereditary and environmental components, schizophrenia must be understood across multiple biological scales, from genes through cells and circuits to behaviors. The key to evaluating candidate explanatory models, therefore, is to establish causal links between disease-related phenomena observed across these scales. To this end, there has been a resurgence of interest in the circuit-level pathophysiology of schizophrenia, which has the potential to link molecular and cellular data from risk factor and post-mortem studies with the behavioral phenomena that plague patients. The demonstration that patients with schizophrenia frequently have deficits in neuronal synchrony, including deficits in local oscillations and long-range functional connectivity, offers a promising opportunity to forge such links across scales.

Neurophysiological characterization of high-dose magnetic seizure therapy: comparisons with electroconvulsive shock and cognitive outcomes.

Magnetic seizure therapy (MST) is under development as a means of improving cognitive outcomes with convulsive therapy through achieving better control over therapeutic seizure induction than is possible with conventional electroconvulsive therapy. In this investigation, we present the first neurophysiological characterization of high-dose MST (HD-MST, 6× seizure threshold) to see if a higher dose that is often used in human trials retains differential expression relative to electroconvulsive shock (ECS) and to explore the relationship between seizure expression and cognitive outcomes. To this end, rhesus monkeys received 4 weeks of daily treatment with ECS, HD-MST, and anesthesia-alone sham in counterbalanced order, with an interposed recovery period. Two channels of electroencephalogram were recorded during and immediately after the ictal period. Electroencephalogram power within delta, theta, alpha, and beta frequency bands was calculated. Electroconvulsive shock showed significantly more ictal power in all frequency bands than HD-MST (P < 0.01). Electroencephalogram power during the postictal period was significantly different among conditions only for the delta band. Higher ictal expression with ECS was associated with slowed completion time for an orientation task given immediately after the treatments. Our results support earlier findings demonstrating that MST- and ECS-induced seizures elicit differential patterns of ictal expression, consistent with the relatively more superficial stimulation achieved via magnetic induction in comparison with conventional electroconvulsive therapy. These results demonstrate that MST, even at high dose, results in seizures that differ neurophysiologically from ECS. It further suggests that some of the differences in ictal expression may relate to the improved cognitive outcomes seen with MST.

Electrophysiological Endophenotypes in Rodent Models of Schizophrenia and Psychosis

Schizophrenia is caused by a diverse array of risk factors and results in a similarly diverse set of symptoms. Electrophysiological endophenotypes lie between risks and symptoms and have the potential to link the two. Electrophysiological studies in rodent models, described here, demonstrate that widely differing risk factors result in a similar set of core electrophysiological endophenotypes, suggesting the possibility of a shared neurobiological substrate.