Timing, or the decision of when to act, is essential to mammalian behaviors from escaping predators to driving a car. It requires cognitive functions such as working memory for time-based rules and attention to the passing of time. Thus, it can be used as a proxy for higher order executive functions that are difficult to measure but are impaired in many neurological disorders. Therefore, insights from studies of interval timing, tasks which require estimating time intervals of several seconds, have great value for our understanding of human disease. Crucial to timing is the basal ganglia, which integrates cortical activity with midbrain dopamine signals and sends out signals to the spinal cord that regulate movement, motivation, and other behaviors. We have previously found that within the basal ganglia, medium spiny neurons of the striatum exhibit ramping activity in time-related tasks. In other words, they gradually increase or decrease firing frequency across a timed interval, and this is thought to encode time. Yet it is still unknown how the encoding of time is translated into time-based motor responses. To answer this question, we turned to the external globus pallidus (GPe) because it is a regulatory hub within the basal ganglia and is thus well positioned to regulate timing behavior. We sought to examine how the GPe functions in response to time-based demands.

We recorded from neuronal ensembles using 16 channel electrode arrays implanted in the GPe of five mice while they performed an interval timing task called the switch interval timing task. Spike sorting was then used to identify signal from individual neurons.

Data were compiled from 43 neurons over several trials. Principal component analysis of neural firing activity was then conducted and revealed a downward ramping pattern in GPe neurons during interval timing trials. Data were then separated based on trials in which mice made correct decisions and those in which mice made a mistake. We found that when mice make correct timing decisions, there is downward ramping activity in the GPe, yet when mice make timing mistakes, this ramping pattern is lost.

Our findings suggest that the GPe processes timing signals through ramping activity, before projecting to the output nuclei of the basal ganglia. This is a novel finding and contributes to a growing understanding of the temporal code of the basal ganglia. The full extent of this code is still unknown, but this insight contributes to a better understanding of how the globus pallidus represents cognition. If we can better explain the neural correlates of timing, we can use this knowledge to inform therapeutic interventions for basal ganglia dysfunction, which could have profound implications for diseases like Parkinson’s disease, which affects millions around the world.

Quantitative susceptibility mapping (QSM) demonstrates elevated iron content in Parkinson’s disease (PD) patients within the basal ganglia, though it has infrequently been studied in relation to gait difficulties including freezing of gait (FOG). Our purpose was to relate QSM of basal ganglia and extra-basal ganglia structures with qualitative and quantitative gait measures in PD.

This case–control study included PD and cognitively unimpaired (CU) participants from the Comprehensive Assessment of Neurodegeneration and Dementia study. Whole brain QSM was acquired at 3T. Region of interests (ROIs) were drawn blinded manually in the caudate nucleus, putamen, globus pallidus, pulvinar nucleus of the thalamus, red nucleus, substantia nigra, and dentate nucleus. Susceptibilities of ROIs were compared between PD and CU. Items from the FOG questionnaire and quantitative gait measures from PD participants were compared to susceptibilities.

Twenty-nine participants with PD and 27 CU participants were included. There was no difference in susceptibility values in any ROI when comparing CU versus PD (p > 0.05 for all). PD participants with gait impairment (n = 23) had significantly higher susceptibility in the putamen (p = 0.008), red nucleus (p = 0.01), and caudate nucleus (p = 0.03) compared to those without gait impairment (n = 6). PD participants with FOG (n = 12) had significantly higher susceptibility in the globus pallidus (p = 0.03) compared to those without FOG (n = 17). Among quantitative gait measures, only stride time variability was significantly different between those with and without FOG (p = 0.04).

Susceptibilities in basal ganglia and extra-basal ganglia structures are related to qualitative measures of gait impairment and FOG in PD.

Anxiety can interfere with attention and working memory, which are components that affect learning. Statistical models have been designed to study learning, such as the Bayesian Learning Model, which takes into account prior possibilities and behaviours to determine how much of a new behaviour is determined by learning instead of chance. However, the neurobiological basis underlying how anxiety interferes with learning is not yet known. Accordingly, we aimed to use neuroimaging techniques and apply a Bayesian Learning Model to study learning in individuals with generalised anxiety disorder (GAD).

Participants were 25 controls and 14 individuals with GAD and comorbid disorders. During fMRI, participants completed a shape-button association learning and reversal task. Using a flexible factorial analysis in SPM, activation in the dorsolateral prefrontal cortex, basal ganglia, and hippocampus was compared between groups during first reversal. Beta values from the peak of these regions were extracted for all learning conditions and submitted to repeated measures analyses in SPSS.

Individuals with GAD showed less activation in the basal ganglia and the hippocampus only in the first reversal compared with controls. This difference was not present in the initial learning and second reversal.

Given that the basal ganglia is associated with initial learning, and the hippocampus with transfer of knowledge from short- to long-term memory, our results suggest that GAD may engage these regions to a lesser extent during early accommodation or consolidation of learning, but have no longer term effects in brain activation patterns during subsequent learning.

Iron plays a key role in a broad set of metabolic processes. Iron deficiency is the most common nutritional deficiency in the world, but its neuropsychiatric implications in adolescents have not been examined.

Twelve- to 17-year-old unmedicated females with major depressive or anxiety disorders or with no psychopathology underwent a comprehensive psychiatric assessment for this pilot study. A T1-weighted magnetic resonance imaging scan was obtained, segmented using Freesurfer. Serum ferritin concentration (sF) was measured. Correlational analyses examined the association between body iron stores, psychiatric symptom severity, and basal ganglia volumes, accounting for confounding variables.

Forty females were enrolled, 73% having a major depressive and/or anxiety disorder, 35% with sF < 15 ng/mL, and 50% with sF < 20 ng/mL. Serum ferritin was inversely correlated with both anxiety and depressive symptom severity (r = −0.34, p < 0.04 and r = −0.30, p < 0.06, respectively). Participants with sF < 15 ng/mL exhibited more severe depressive and anxiety symptoms as did those with sF < 20 ng/mL. Moreover, after adjusting for age and total intracranial volume, sF was inversely associated with left caudate (Spearman's r = −0.46, p < 0.04), left putamen (r = −0.58, p < 0.005), and right putamen (r = −0.53, p < 0.01) volume.

Brain iron may become depleted at a sF concentration higher than the established threshold to diagnose iron deficiency (i.e. 15 ng/mL), potentially disrupting brain maturation and contributing to the emergence of internalizing disorders in adolescents.

Progressive brain structural MRI changes are described in schizophrenia and have been ascribed to both illness progression and antipsychotic treatment. We investigated treatment effects, in terms of total cumulative antipsychotic dose, efficacy and tolerability, on brain structural changes over the first 24 months of treatment in schizophrenia.

A prospective, 24-month, single-site cohort study in 99 minimally treated patients with first-episode schizophrenia, schizophreniform and schizoaffective disorder, and 98 matched healthy controls. We treated the patients according to a fixed protocol with flupenthixol decanoate, a long-acting injectable antipsychotic. We assessed psychopathology, cognition, extrapyramidal symptoms and BMI, and acquired MRI scans at months 0, 12 and 24. We selected global cortical thickness, white matter volume and basal ganglia volume as the regions of interest.

The only significant group × time interaction was for basal ganglia volumes. However, patients, but not controls, displayed cortical thickness reductions and increases in white matter and basal ganglia volumes. Cortical thickness reductions were unrelated to treatment. White matter volume increases were associated with lower cumulative antipsychotic dose, greater improvements in psychopathology and cognition, and more extrapyramidal symptoms. Basal ganglia volume increases were associated with greater improvements in psychopathology, greater increases in BMI and more extrapyramidal symptoms.

We provide evidence for plasticity in white matter and basal ganglia associated with antipsychotic treatment in schizophrenia, most likely linked to the dopamine blocking actions of these agents. Cortical changes may be more closely related to the neurodevelopmental, non-dopaminergic aspects of the illness.

To investigate the frequency of bradykinesia in patients with obsessive-compulsive disorder (OCD) and to see whether patients with OCD who also have bradykinesia display distinctive neuropsychological and neuropsychiatric features.

We studied 23 antipsychotic-free patients with OCD and 13 healthy controls. Bradykinesia was assessed with section III of the Unified Parkinson Disease Rating Scale. The Wechsler Adult Intelligent Scales-Revised (WAIS-R) was used to assess the Full Scale IQ and to measure visuospatial, visuoconstructional ability and psychomotor speed/mental slowness.

Of the 23 patients with OCD studied, 8 (34%) had mild symptoms of bradykinesia. No relationship was found between bradykinesia and the sociodemographic variables assessed but this motor symptom was significantly associated with the severity of compulsions. Patients with bradykinesia differed from those without: they had a higher frequency of repeating compulsions, and lower IQ scores, performance scores, and WAIS-R subtest scores for similarities and picture completion. No significant differences were found between patients without bradykinesia and healthy controls in any test.

Clinical assessment of motor symptoms in adult patients with OCD often discloses mild bradykinesia sometimes associated with repeating compulsions and poor WAIS-R performance scores.

The polymorphism rs1006737 within the CACNA1C gene is associated with increased risk for bipolar disorder (BD) and variations in brain morphology and function of subcortical regions. Here we sought to investigate the influence of CACNA1C polymorphism on key subcortical brain structures implicated in the pathophysiology of BD.

Structural magnetic resonance imaging scans were acquired from 41 euthymic patients with BD and 40 healthy controls, who were also genotyped for the CACNA1C rs1006737 polymorphism. The effect of diagnosis, genotype and their interaction was examined in predefined volumes of interest in the basal ganglia, hypothalamus and amygdala extracted using SPM5.

Carriers of the CACNA1C rs1006737 risk allele showed increased grey matter density in the right amygdala and right hypothalamus irrespective of diagnosis. An interaction between genotype and diagnosis was observed in the left putamen which was smaller in BD patients carrying the risk allele than in healthy controls.

The CACNA1C rs1006737 polymorphism influences anatomical variation within subcortical regions involved in emotional processing.