Implicit sequence learning and working memory: correlated or complicated?

The relationship between implicit/incidental sequence learning and working memory motivated a series of research because it is plausible that higher working memory capacity opens a “larger window” to a sequence, allowing thereby the sequence learning process to be easier. Although the majority of studies found no relationship between implicit sequence learning and working memory capacity, in the past few years several studies have tried to demonstrate the shared or partly shared brain networks underlying these two systems. In order to help the interpretation of these and future results, in this mini-review we suggest the following factors to be taken into consideration before testing the relationship between sequence learning and working memory: 1) the explicitness of the sequence; 2) the method of measuring working memory capacity; 3) online and offline stages of sequence learning; and 4) general skill- and sequence-specific learning

Striatal GABA-MRS predicts response inhibition performance and its cortical electrophysiological correlates

Response inhibition processes are important for performance monitoring and are mediated via a network constituted by different cortical areas and basal ganglia nuclei. At the basal ganglia level, striatal GABAergic medium spiny neurons are known to be important for response selection, but the importance of the striatal GABAergic system for response inhibition processes remains elusive. Using a novel combination of behavior al, EEG and magnetic resonance spectroscopy (MRS) data, we examine the relevance of the striatal GABAergic system for response inhibition processes. The study shows that striatal GABA levels modulate the efficacy of response inhibition processes. Higher striatal GABA levels were related to better response inhibition performance. We show that striatal GABA modulate specific subprocesses of response inhibition related to pre-motor inhibitory processes through the modulation of neuronal synchronization processes. To our knowledge, this is the first study providing direct evidence for the relevance of the striatal GABAergic system for response inhibition functions and their cortical electrophysiological correlates in humans

Striatal and thalamic GABA level concentrations play differential roles for the modulation of response selection processes by proprioceptive information.

The selection of appropriate responses is a complex endeavor requiring the integration of many different sources of information in fronto-striatal-thalamic circuits. An often neglected but relevant piece of information is provided by proprioceptive inputs about the current position of our limbs. This study examines the importance of striatal and thalamic GABA levels in these processes using GABA-edited magnetic resonance spectroscopy (GABAMRS) and a Simon task featuring proprioception-induced interference in healthy subjects. As a possible model of deficits in the processing of proprioceptive information, we also included Parkinson's disease (PD) patients in this study.The results show that proprioceptive information about unusual postures complicates response selection processes in controls, but not in PD patients. The well-known deficits of PD patients in processing proprioceptive information can turn into a benefit when altered proprioceptive information would normally complicate response selection processes. Striatal and thalamic GABA levels play dissociable roles in the modulation of response selection processes by proprioceptive information: Striatal GABA levels seem to be important for the general speed of responding, most likely because striatal GABA promotes response selection. In contrast, the modulation of response conflict by proprioceptive information is closely related to thalamic GABA concentrations with higher concentration being related to a smaller response conflict effect. The most likely explanation for this finding is that the thalamus is involved in the integration of sensorimotor, attentional, and cognitive information for the purpose of response formation. Yet, this effect in the thalamus vanishes when controls and PD patients were analyzed separately

Dual tasking impairments are associated with striatal pathology in Huntington’s disease

Background: Recent findings suggest that individuals with Huntington’s disease (HD) have an impaired capacity to execute cognitive and motor tasks simultaneously, or dual task, which gradually worsens as the disease advances. The onset and neuropathological changes mediating impairments in dual tasking in individuals with HD are unclear. The reliability of dual tasking assessments for individuals with HD is also unclear. Objectives: To evaluate differences in dual tasking performance between individuals with HD (presymptomatic and prodromal) and matched controls, to investigate associations between striatal volume and dual tasking performance, and to determine the reliability of dual tasking assessments. Methods: Twenty individuals with HD (10 presymptomatic and 10 prodromal) and 20 healthy controls were recruited for the study. Individuals undertook four single and dual task assessments, comprising motor (postural stability or force steadiness) and cognitive (simple or complex mental arithmetic) components, with single and dual tasks performed three times each. Participants also undertook a magnetic resonance imaging assessment. Results: Compared to healthy controls, individuals with presymptomatic and prodromal HD displayed significant deficits in dual tasking, particularly cognitive task performance when concurrently undertaking motor tasks (P \u3c 0.05). The observed deficits in dual tasking were associated with reduced volume in caudate and putamen structures (P \u3c 0.05),however, not with clinical measures of disease burden. An analysis of the reliability of dual tasking assessments revealed moderate to high test–retest reliability [ICC: 0.61-0.99] for individuals with presymptomatic and prodromal HD and healthy controls. Conclusions: Individuals with presymptomatic and prodromal HD have significant deficits in dual tasking that are associated with striatal degeneration. Findings also indicate that dual tasking assessments are reliable in individuals presymptomatic and prodromal HD and healthy controls

Increasing striatal dopamine release through repeated bouts of theta burst transcranial magnetic stimulation of the left dorsolateral prefrontal cortex. A 18F-desmethoxyfallypride positron emission tomography study

IntroductionTranscranial Magnetic Stimulation (TMS) can modulate fronto-striatal connectivity in the human brain. Here Positron Emission Tomography (PET) and neuro-navigated TMS were combined to investigate the dynamics of the fronto-striatal connectivity in the human brain. Employing 18F-DesmethoxyFallypride (DMFP) – a Dopamine receptor-antagonist – the release of endogenous dopamine in the striatum in response to time-spaced repeated bouts of excitatory, intermittent theta burst stimulation (iTBS) of the Left-Dorsolateral Prefrontal Cortex (L-DLPFC) was measured.Methods23 healthy participants underwent two PET sessions, each one with four blocks of iTBS separated by 30 minutes: sham (control) and verum (90% of individual resting motor threshold). Receptor Binding Ratios were collected for sham and verum sessions across 37 time frames (about 130 minutes) in striatal sub-regions (Caudate nucleus and Putamen).ResultsVerum iTBS increased the dopamine release in striatal sub-regions, relative to sham iTBS. Dopamine levels in the verum session increased progressively across the time frames until frame number 28 (approximately 85 minutes after the start of the session and after three iTBS bouts) and then essentially remained unchanged until the end of the session.ConclusionResults suggest that the short-timed iTBS protocol performed in time-spaced blocks can effectively induce a dynamic dose dependent increase in dopaminergic fronto-striatal connectivity. This scheme could provide an alternative to unpleasant and distressing, long stimulation protocols in experimental and therapeutic settings. Specifically, it was demonstrated that three repeated bouts of iTBS, spaced by short intervals, achieve larger effects than one single stimulation. This finding has implications for the planning of therapeutic interventions, for example, treatment of major depression

A perspective on neural and cognitive mechanisms of error commission

Behavioral adaptation and cognitive control are crucial for goal-reaching behaviors. Every creature is ubiquitously faced with choices between behavioral alternatives. Common sense suggests that errors are an important source of information in the regulation of such processes. Several theories exist regarding cognitive control and the processing of undesired outcomes. However, most of these models focus on the consequences of an error, and less attention has been paid to the mechanisms that underlie the commissioning of an error. In this article, we present an integrative review of neuro-cognitive models that detail the determinants of the occurrence of response errors. The factors that may determine the likelihood of committing errors are likely related to the stability of task-representations in prefrontal networks, attentional selection mechanisms and mechanisms of action selection in basal ganglia circuits. An important conclusion is that the likelihood of committing an error is not stable over time but rather changes depending on the interplay of different functional neuro-anatomical and neuro-biological systems. We describe factors that might determine the time-course of cognitive control and the need to adapt behavior following response errors. Finally, we outline the mechanisms that may proof useful for predicting the outcomes of cognitive control and the emergence of response errors in future research

Neurobiological mechanisms of control in alcohol use disorder – Moving towards mechanism-based non-invasive brain stimulation treatments

Alcohol use disorder (AUD) is characterized by excessive habitual drinking and loss of control over alcohol intake despite negative consequences. Both of these aspects foster uncontrolled drinking and high relapse rates in AUD patients. Yet, common interventions mostly focus on the phenomenological level, and prioritize the reduction of craving and withdrawal symptoms. Our review provides a mechanistic understanding of AUD and suggests alternative therapeutic approaches targeting the mechanisms underlying dysfunctional alcohol-related behaviours. Specifically, we explain how repeated drinking fosters the development of rigid drinking habits and is associated with diminished cognitive control. These behavioural and cognitive effects are then functionally related to the neurobiochemical effects of alcohol abuse. We further explain how alterations in fronto-striatal network activity may constitute the neurobiological correlates of these alcohol-related dysfunctions. Finally, we discuss limitations in current pharmacological AUD therapies and suggest non-invasive brain stimulation (like TMS and tDCS interventions) as a potential addition/alternative for modulating the activation of both cortical and subcortical areas to help re-establish the functional balance between controlled and automatic behaviour

Selbstgespür und neuronale Korrelate der exekutiven Kontrolle bei Patienten mit unipolarer Depression: Eine EEG-Studie unter Verwendung des Flanker-Paradigmas.

Die Depression ist eine der schwerwiegendsten psychiatrischen Erkrankungen des 21. Jahrhunderts. Diese oft chronische Erkrankung verursacht eine starke Beeinträchtigung der Lebensqualität sowie erhebliche Kosten für die Gesundheitssysteme weltweit. Neben Anhedonie, Niedergeschlagenheit und Antriebslosigkeit berichten die meisten depressiven Patienten von Konzentrationsstörungen und verminderter Entscheidungsfähigkeit. Bisherige Studien konnten zeigen, dass Depressivität mit Defiziten der exekutiven Funktion assoziiert ist. Unterschiedliche experimentelle Paradigmen, insbesondere das Go-Nogo- oder das Flanker-Paradigma, sind entwickelt worden, um exekutive Funktionen zu testen. Bildgebende Studien konnten durch die Kombination von fMRT mit den zuvor genannten Paradigmen neuronale Korrelate der exekutiven Funktion ermitteln. Diese Studien zeigten, dass insbesondere der anteriore cinguläre sowie der präfrontale Cortex bei Depressiven beeinträchtigt zu sein scheinen. Auch mit Hilfe von ereigniskorrelierten Potentialen konnten in EEG-Studien Defizite der exekutiven Funktion bei depressiven Patienten bestätigt werden. Die Ergebnisse der neurophysiologischen Forschung hierzu sind bisher jedoch noch nicht einheitlich. Darüber hinaus gibt es Hinweise auf den Zusammenhang zwischen bestimmten Persönlichkeitsmerkmalen und der Depressivität. Über diese, möglicherweise entscheidende Verbindung ist bisher jedoch nur sehr wenig bekannt, sodass weitere Studien benötigt werden. In dieser Arbeit wurde die Beziehung zwischen Hirnfunktion, Depressivität und Persönlichkeit untersucht. Hierzu wurde an einer Gruppe von 24 depressiven Patienten und 24 gesunden Probanden während der Durchführung des Kopp-Flanker-Paradigmas zur Testung der exekutiven Funktion ein EEG abgeleitet. Um die Selbstregulationsfunktionen der Teilnehmer zu bestimmen, wurde das Selbststeuerungsinventar nach Kuhl und Fuhrmann verwendet. Die Untersuchung zeigte keine Gruppenunterschiede in den Reaktionszeiten, jedoch erhöhte Fehlerraten in der Gruppe der depressiven Patienten. Darüber hinaus zeigte sich eine verminderte P3-Komponente bei den depressiven Patienten, während die N2-Komponente unbeeinflusst zu sein scheint. Die Untersuchung der Selbststeuerung im Zusammenspiel mit den bereits genannten Befunden weist darauf hin, dass die Beziehung zwischen Hirnfunktion und Depressivität durch das Maß an Selbstgespür vermittelt wird

White Matter Degeneration in Huntington's Disease: A Study of Brain Structure and Cognition

Huntington's disease (HD) is a hereditary neurodegenerative disorder characterised by devastating physical, behavioural and mental dysfunction. Accumulating evidence indicates that abnormal white matter (WM) is a major hallmark of the disease, with both macro- and microstructural changes apparent before manifest diagnosis. This thesis is an investigation of WM in HD and uses various imaging and cognitive techniques to address some key challenges. Firstly, the development of reliable structural measurement techniques sensitive to longitudinal change may aid characterisation of subtle abnormalities before disease onset. Secondly, optimised diffusion imaging techniques which incorporate superior image processing tools will further understanding as to why changes are harder to find in the premanifest stage and will increase sensitivity to detect them. Thirdly, the development of novel, hypothesis-driven neuropsychological tasks will help detect heterogeneous cognitive decline in individuals in the earliest disease stages. To address these challenges, firstly, a novel corpus callosum (CC) segmentation technique is developed and applied to a large clinical cohort revealing disease-related reduction in baseline CC volume and elevated rates of change over 24 months in both premanifest and manifest HD participants. Secondly, an investigation of template effects in diffusion image analysis reveals consistency between analyses using three customised templates and evidence of the superiority of tensor-based registration over scalar-based registration is demonstrated. An exploratory investigation into the association between brain volume and WM diffusivity is also presented and disease-specific changes in HD gene-carriers are reported. Lastly, two specially designed, pathology-targeted cognitive tasks are applied to a premanifest HD cohort. Abnormal interhemispheric transfer from the non-dominant to dominant hemisphere as well as altered attentional processing and impaired automaticity is revealed. By developing techniques to characterise WM pathology and explore cognitive deficits, this thesis improves our understanding of the role of WM degeneration in the premanifest and early stages of HD