Altered brainstem responses to modafinil in schizophrenia: implications for adjunctive treatment of cognition.

Candidate pro-cognitive drugs for schizophrenia targeting several neurochemical systems have consistently failed to demonstrate robust efficacy. It remains untested whether concurrent antipsychotic medications exert pharmacodynamic interactions that mitigate pro-cognitive action in patients. We used functional MRI (fMRI) in a randomized, double-blind, placebo-controlled within-subject crossover test of single-dose modafinil effects in 27 medicated schizophrenia patients, interrogating brainstem regions where catecholamine systems arise to innervate the cortex, to link cellular and systems-level models of cognitive control. Modafinil effects were evaluated both within this patient group and compared to a healthy subject group. Modafinil modulated activity in the locus coeruleus (LC) and ventral tegmental area (VTA) in the patient group. However, compared to the healthy comparison group, these effects were altered as a function of task demands: the control-independent drug effect on deactivation was relatively attenuated (shallower) in the LC and exaggerated (deeper) in the VTA; in contrast, again compared to the comparison group, the control-related drug effects on positive activation were attenuated in LC, VTA and the cortical cognitive control network. These altered effects in the LC and VTA were significantly and specifically associated with the degree of antagonism of alpha-2 adrenergic and dopamine-2 receptors, respectively, by concurrently prescribed antipsychotics. These sources of evidence suggest interacting effects on catecholamine neurons of chronic antipsychotic treatment, which respectively increase and decrease sustained neuronal activity in LC and VTA. This is the first direct evidence in a clinical population to suggest that antipsychotic medications alter catecholamine neuronal activity to mitigate pro-cognitive drug action on cortical circuits

Proactive and reactive cognitive control and dorsolateral prefrontal cortex dysfunction in first episode schizophrenia.

Cognitive control deficits have been consistently documented in patients with schizophrenia. Recent work in cognitive neuroscience has hypothesized a distinction between two theoretically separable modes of cognitive control-reactive and proactive. However, it remains unclear the extent to which these processes are uniquely associated with dysfunctional neural recruitment in individuals with schizophrenia. This functional magnetic resonance imaging (fMRI) study utilized the color word Stroop task and AX Continuous Performance Task (AX-CPT) to tap reactive and proactive control processes, respectively, in a sample of 54 healthy controls and 43 patients with first episode schizophrenia. Healthy controls demonstrated robust dorsolateral prefrontal, anterior cingulate, and parietal cortex activity on both tasks. In contrast, patients with schizophrenia did not show any significant activation during proactive control, while showing activation similar to control subjects during reactive control. Critically, an interaction analysis showed that the degree to which prefrontal activity was reduced in patients versus controls depended on the type of control process engaged. Controls showed increased dorsolateral prefrontal cortex (DLPFC) and parietal activity in the proactive compared to the reactive control task, whereas patients with schizophrenia did not demonstrate this increase. Additionally, patients' DLPFC activity and performance during proactive control was associated with disorganization symptoms, while no reactive control measures showed this association. Proactive control processes and concomitant dysfunctional recruitment of DLPFC represent robust features of schizophrenia that are also directly associated with symptoms of disorganization

Concomitant medication use and clinical outcome of repetitive Transcranial Magnetic Stimulation (rTMS) treatment of Major Depressive Disorder.

BackgroundRepetitive Transcranial Magnetic Stimulation (rTMS) is commonly administered to Major Depressive Disorder (MDD) patients taking psychotropic medications, yet the effects on treatment outcomes remain unknown. We explored how concomitant medication use relates to clinical response to a standard course of rTMS.MethodsMedications were tabulated for 181 MDD patients who underwent a six-week rTMS treatment course. All patients received 10 Hz rTMS administered to left dorsolateral prefrontal cortex (DLPFC), with 1 Hz administered to right DLPFC in patients with inadequate response to and/or intolerance of left-sided stimulation. Primary outcomes were change in Inventory of Depressive Symptomatology Self Report (IDS-SR30) total score after 2, 4, and 6 weeks.ResultsUse of benzodiazepines was associated with less improvement at week 2, whereas use of psychostimulants was associated with greater improvement at week 2 and across 6 weeks. These effects were significant controlling for baseline variables including age, overall symptom severity, and severity of anxiety symptoms. Response rates at week 6 were lower in benzodiazepine users versus non-users (16.4% vs. 35.5%, p = 0.008), and higher in psychostimulant users versus non-users (39.2% vs. 22.0%, p = 0.02).ConclusionsConcomitant medication use may impact rTMS treatment outcome. While the differences reported here could be considered clinically significant, results were not corrected for multiple comparisons and findings should be replicated before clinicians incorporate the evidence into clinical practice. Prospective, hypothesis-based treatment studies will aid in determining causal relationships between medication treatments and outcome

Modafinil modulation of the default mode network

RationaleThe default mode network (DMN) is a functional network which is implicated in a range of cognitive processes. This network is proposed to consist of hubs located in the ventromedial prefrontal cortex (vmPFC), posterior cingulate/retrosplenial cortex (PCC/rSpl), and inferior parietal lobule (IPL), with other midline cortical and temporal lobe nodes connected to these hubs. How this network is modulated by neurochemical systems during functional brain activity is not yet understood.ObjectivesIn the present study, we used the norepinephrine/dopamine transporter inhibitor modafinil to test the hypothesis that this drug modulates the DMN.MethodsEighteen healthy right-handed adults participated in a double-blind, placebo-controlled study of single oral dose modafinil 200 mg. They performed a simple visual sensorimotor task during slow event-related fMRI. Drug effects were interrogated within the DMN defined by task-induced deactivation (TID) on placebo.ResultsThere was a trend toward faster reaction time (RT) on modafinil (Cohen's d = 0.38). Brain regions within the DMN which exhibited significant modafinil-induced augmentation of TID included vmPFC, PCC/rSpl, and left IPL. Across subjects, the modafinil effect on TID in the vmPFC was significantly and specifically associated with drug effects on RT speeding.ConclusionsModafinil augments TID in the DMN to facilitate sensorimotor processing speed, an effect which may be particularly dependent on changes in vmPFC activity. This is consistent with the gain control function of catecholamine systems and may represent an important aspect of the pro-cognitive effects of modafinil

Towards responsible use of cognitive-enhancing drugs by the healthy

In this article, we propose actions that will help society accept the benefits of enhancement, given appropriate research and evolved regulation. Prescription drugs are regulated as such not for their enhancing properties but primarily for considerations of safety and potential abuse. Still, cognitive enhancement has much to offer individuals and society, and a proper societal response will involve making enhancements available while managing their risks

Reduction of Pavlovian bias in schizophrenia: Enhanced effects in clozapine-administered patients

The negative symptoms of schizophrenia (SZ) are associated with a pattern of reinforcement learning (RL) deficits likely related to degraded representations of reward values. However, the RL tasks used to date have required active responses to both reward and punishing stimuli. Pavlovian biases have been shown to affect performance on these tasks through invigoration of action to reward and inhibition of action to punishment, and may be partially responsible for the effects found in patients. Forty-five patients with schizophrenia and 30 demographically-matched controls completed a four-stimulus reinforcement learning task that crossed action ("Go" or "NoGo") and the valence of the optimal outcome (reward or punishment-avoidance), such that all combinations of action and outcome valence were tested. Behaviour was modelled using a six-parameter RL model and EEG was simultaneously recorded. Patients demonstrated a reduction in Pavlovian performance bias that was evident in a reduced Go bias across the full group. In a subset of patients administered clozapine, the reduction in Pavlovian bias was enhanced. The reduction in Pavlovian bias in SZ patients was accompanied by feedback processing differences at the time of the P3a component. The reduced Pavlovian bias in patients is suggested to be due to reduced fidelity in the communication between striatal regions and frontal cortex. It may also partially account for previous findings of poorer "Go-learning" in schizophrenia where "Go" responses or Pavlovian consistent responses are required for optimal performance. An attenuated P3a component dynamic in patients is consistent with a view that deficits in operant learning are due to impairments in adaptively using feedback to update representations of stimulus value