Striatal Loops Research Articles

High-dimensional Metaverse Platforms and the Virtually Extended Self.

The study of cognition has traditionally used low-dimensional measures and stimulus presentations that emphasize laboratory control over high-dimensional (i.e., ecologically valid) tools that reflect the activities and interactions in everyday living. Although controlled experimental presentations in laboratories have enhanced our understanding of cognition for both healthy and clinical cohorts, high dimensionality may extend reality and cognition. High-dimensional Metaverse approaches use extended reality (XR) platforms with dynamic stimulus presentations that couple humans and simulation technologies to extend cognition. The plan for this paper is as follows: The "Extending from low to high-dimensional studies of cognition" section discusses current needs for high-dimensional stimulus presentations that reflect everyday cognitive activities. In the "Algorithmic devices and digital extension of cognition" section, technologies of the extended mind are introduced with the Metaverse as a candidate cognitive process for extension. Next, in the "A neurocognitive framework for understanding technologies of the extended mind" section, a framework and model are proposed for understanding the neural correlates of human technology couplings in terms of automatic algorithmic processes (limbic-ventral striatal loop); reflective cognition (prefrontal-dorsal striatal loop); and algorithmic processing (insular cortex). The algorithmic processes of human-technology interactions can, over time, become an automated and algorithmic coupling of brain and technology. The manuscript ends with a brief summary and discussion of the ways in which the Metaverse can be used for studying how persons respond to high-dimensional stimuli in simulations that approximate real-world activities and interactions.

Dopamine depletion leads to pathological synchronization of distinct basal ganglia loops in the beta band.

Motor symptoms of Parkinson's Disease (PD) are associated with dopamine deficits and pathological oscillation of basal ganglia (BG) neurons in the β range ([12-30] Hz). However, how dopamine depletion affects the oscillation dynamics of BG nuclei is still unclear. With a spiking neurons model, we here capture the features of BG nuclei interactions leading to oscillations in dopamine-depleted condition. We highlight that both the loop between subthalamic nucleus (STN) and Globus Pallidus pars externa (GPe) and the loop between striatal fast spiking and medium spiny neurons and GPe display resonances in the β range, and synchronize to a common β frequency through interaction. Crucially, the synchronization depends on dopamine depletion: the two loops are largely independent for high levels of dopamine, but progressively synchronize as dopamine is depleted due to the increased strength of the striatal loop. The model is validated against recent experimental reports on the role of cortical inputs, STN and GPe activity in the generation of β oscillations. Our results highlight the role of the interplay between the GPe-STN and the GPe-striatum loop in generating sustained β oscillations in PD subjects, and explain how this interplay depends on the level of dopamine. This paves the way to the design of therapies specifically addressing the onset of pathological β oscillations.

A striatal SOM-driven ChAT-iMSN loop generates beta oscillations and produces motor deficits.

Enhanced beta oscillations within the cortico-basal ganglia-thalamic (CBT) network are correlated with motor deficits in Parkinson's disease (PD), whose generation has been associated recently with amplified network dynamics in the striatum. However, how distinct striatal cell subtypes interact to orchestrate beta oscillations remains largely unknown. Here, we show that optogenetic suppression of dopaminergic control over the dorsal striatum (DS) elevates the power of local field potentials (LFPs) selectively at beta band (12-25Hz), accompanied by impairments in locomotion. The amplified beta power originates from a striatal loop driven by somatostatin-expressing (SOM) interneurons and constituted by choline acetyltransferase (ChAT)-expressing interneurons and dopamine D2 receptor (D2R)-expressing medium spiny neurons (iMSNs). Moreover, closed-loop intervention selectively targeting striatal iMSNs or ChATs diminishes beta oscillations and restores motor function. Thus, we reveal a striatal microcircuit motif that underlies beta oscillation generation and accompanied motor deficits upon perturbation of dopaminergic control over the striatum.

Alterations of Striatal Subregions in a Prion Protein Gene V180I Mutation Carrier Presented as Frontotemporal Dementia With Parkinsonism.

ObjectiveTo explore the roles of striatal subdivisions in the pathogenesis of frontotemporal dementia with parkinsonism (FTDP) in a patient resulting from prion protein gene (PRNP) mutation.MethodsThis patient received clinical interviews and underwent neuropsychological assessments, genetic testing, [18F]-fluorodeoxyglucose positron emission tomography ([18F]-FDG PET)/MRI, and [18F]-dihydrotetrabenazine positron emission tomography ([18F]-DTBZ PET)/CT. Region-of-interest analysis was conducted concerning metabolism, and dopamine transport function between this patient and 12 controls, focusing on the striatum subregions according to the Oxford-GSK-Imanova Striatal Connectivity Atlas.ResultsA 64-year-old man initially presented with symptoms of motor dysfunction and subsequently behavioral and personality changes. FTDP was initially suspected. Sequence analysis disclosed a valine to isoleucine at codon 180 in PRNP. Compared to controls, this patient had a severe reduction (> 2SD) of standard uptake value ratio (SUVR) in the limbic and executive subregions but relative retention of metabolism in rostral motor and caudal motor subregions using [18F]-FDG PET/MRI, and the SUVR decreased significantly across the striatal in [18F]-DTBZ PET/CT, especially in the rostral motor and caudal motor subregions.ConclusionThe alteration of frontal striatal loops may be involved in cognitive impairment in FTDP, and the development of parkinsonism in FTDP may be primarily due to the involvement of the presynaptic nigrostriatal loops in PRNP V180I mutation.

Learning, memory and consolidation mechanisms for behavioral control in hierarchically organized cortico-basal ganglia systems.

This article aims to provide a synthesis on the question how brain structures cooperate to accomplish hierarchically organized behaviors, characterized by low‐level, habitual routines nested in larger sequences of planned, goal‐directed behavior. The functioning of a connected set of brain structures—prefrontal cortex, hippocampus, striatum, and dopaminergic mesencephalon—is reviewed in relation to two important distinctions: (a) goal‐directed as opposed to habitual behavior and (b) model‐based and model‐free learning. Recent evidence indicates that the orbitomedial prefrontal cortices not only subserve goal‐directed behavior and model‐based learning, but also code the “landscape” (task space) of behaviorally relevant variables. While the hippocampus stands out for its role in coding and memorizing world state representations, it is argued to function in model‐based learning but is not required for coding of action–outcome contingencies, illustrating that goal‐directed behavior is not congruent with model‐based learning. While the dorsolateral and dorsomedial striatum largely conform to the dichotomy between habitual versus goal‐directed behavior, ventral striatal functions go beyond this distinction. Next, we contextualize findings on coding of reward‐prediction errors by ventral tegmental dopamine neurons to suggest a broader role of mesencephalic dopamine cells, viz. in behavioral reactivity and signaling unexpected sensory changes. We hypothesize that goal‐directed behavior is hierarchically organized in interconnected cortico‐basal ganglia loops, where a limbic‐affective prefrontal‐ventral striatal loop controls action selection in a dorsomedial prefrontal–striatal loop, which in turn regulates activity in sensorimotor‐dorsolateral striatal circuits. This structure for behavioral organization requires alignment with mechanisms for memory formation and consolidation. We propose that frontal corticothalamic circuits form a high‐level loop for memory processing that initiates and temporally organizes nested activities in lower‐level loops, including the hippocampus and the ripple‐associated replay it generates. The evidence on hierarchically organized behavior converges with that on consolidation mechanisms in suggesting a frontal‐to‐caudal directionality in processing control.

Implicit task sequence learning in patients with Parkinson's disease, frontal lesions and amnesia: The critical role of fronto–striatal loops

The purpose of this study was to investigate the role of the fronto–striatal system for implicit task sequence learning. We tested performance of patients with compromised functioning of the fronto–striatal loops, that is, patients with Parkinson's disease and patients with lesions in the ventromedial or dorsolateral prefrontal cortex. We also tested amnesic patients with lesions either to the basal forebrain/orbitofrontal cortex or to thalamic/medio-temporal regions. We used a task sequence learning paradigm involving the presentation of a sequence of categorical binary-choice decision tasks. After several blocks of training, the sequence, hidden in the order of tasks, was replaced by a pseudo-random sequence. Learning (i.e., sensitivity to the ordering) was assessed by measuring whether this change disrupted performance. Although all the patients were able to perform the decision tasks quite easily, those with lesions to the fronto–striatal loops (i.e., patients with Parkinson's disease, with lesions in the ventromedial or dorsolateral prefrontal cortex and those amnesic patients with lesions to the basal forebrain/orbitofrontal cortex) did not show any evidence of implicit task sequence learning. In contrast, those amnesic patients with lesions to thalamic/medio-temporal regions showed intact sequence learning. Together, these results indicate that the integrity of the fronto–striatal system is a prerequisite for implicit task sequence learning.

Olfactory identification deficits and associated response inhibition in obsessive-compulsive disorder: On the scent of the orbitofronto–striatal model

Olfactory identification ability implicates the integrity of the orbitofrontal cortex (OFC). The fronto–striatal circuits including the OFC have been involved in the neuropathology of Obsessive Compulsive Disorder (OCD). However, only a few studies have examined olfactory function in patients with OCD. The Brief Smell Identification Test (B-SIT) and tests from the Cambridge Neuropsychological Automated Battery (CANTAB) were administered to 25 patients with OCD and to 21 healthy matched controls. OCD patients showed a significant impairment in olfactory identification ability as well as widely distributed cognitive deficits in visual memory, executive functions, attention, and response inhibition. The degree of behavioural impairment on motor impulsivity (prolonged response inhibition Stop-Signal Reaction Time) strongly correlated with the B-SIT score. Our study is the first to indicate a shared OFC pathological neural substrate underlying olfactory identification impairment, impulsivity, and OCD. Deficits in visual memory, executive functions and attention further indicate that regions outside of the orbitofronto–striatal loop may be involved in this disorder. Such results may help delineate the clinical complexity of OCD and support more targeted investigations and interventions. In this regard, research on the potential diagnostic utility of olfactory identification deficits in the assessment of OCD would certainly be useful.

Decision-making in normal and pathological aging

Decision making is a complex ability that is likely to be damaged in numerous psychiatric and neurologic disorders and also during the aging process. It therefore implies a large interconnection of cortical and subcortical structures that are directly impacted by the neuroanatomical and neurochemical modifications that occur during the usual or the pathologic aging. Two decision modalities have been isolated, depending on whether the decision making is performed under explicit knowledge of the risks taken or not. In the first case, the decision is taken based on success probabilities and also as a result of preliminary reinforcements (decision under risk). This modality is linked to the executive functions and its neural substrate would be the cognitive frontal striatal loops. In the second case, the decision is exclusively based on preliminary reinforcements (decision under ambiguity) and would be partially independent of cognitive functions. Its neural substrate would be the limbic frontal striatal loops. Nevertheless, the comparison of these hypothesis with the clinical data raises a certain number of controversies. Only the decision making under ambiguity appears to be responsive to the effects of usual aging, suggesting there would be a premature aging of the limbic loops. In Parkinson's disease, controversies appear to know whether the primitive decision impairment concerns the modality under risk or the one under ambiguity, as well as the question of the frontal striatal loops primitively damaged in this pathology pending. Furthermore, the cortical neurodegenerative diseases seem to demonstrate that the decision under ambiguity may be impacted by the cognitive functions, challenging the assumed independency between these two processes. On basis of some studies, the authors suggest to reconsider the links between the decision making, in particular the under ambiguity one and the cognitive functions, questioning how executive functions contribute to this decision modality.

7 Functional magnetic resonance imaging of motor task complexity in Parkinson’s disease

Background Parkinson’s disease (PD), characterized by tremor, bradykinesia and rigidity, was studied as paradigmatic neurologic disease predominantly by functional magnetic resonance imaging (fMRI). The aim of the present study was to study brain areas involved in the planning of motor sequence complexity in PD patients, through a multiple task with increasing difficulty. Proposed methods Eleven PD patients and 11 healthy age and sex-matched subjects served as controls underwent a fMRI design, performing a motor task, consisting of three exercises of increasing difficulty with the right hand. Data analysis of single and multi-task between-group comparison was performed. Results We observed an impairment in activation of frontal–striatal loop and cingulate cortex, with the compensatory function of cerebellum, parietal cortex and supplementary motor area. Multi-task analysis underlined the role of striatal and limbic areas in motor task difficulty. Conclusions The results of the present study are consistent with known results in PD and moreover represent some new evidences, contributing to the comprehension of PD pathophysiology.

Some is not enough: Quantifier comprehension in corticobasal syndrome and behavioral variant frontotemporal dementia

Quantifiers are very common in everyday speech, but we know little about their cognitive basis or neural representation. The present study examined comprehension of three classes of quantifiers that depend on different cognitive components in patients with focal neurodegenerative diseases. Patients evaluated the truth-value of a sentence containing a quantifier relative to a picture illustrating a small number of familiar objects, and performance was related to MRI grey matter atrophy using voxel-based morphometry. We found that patients with corticobasal syndrome (CBS) and posterior cortical atrophy (PCA) are significantly impaired in their comprehension of cardinal quantifiers (e.g. “At least three birds are on the branch”), due in part to their deficit in quantity knowledge. MRI analyses related this deficit to temporal–parietal atrophy found in CBS/PCA. We also found that patients with behavioral variant frontotemporal dementia (bvFTD) are significantly impaired in their comprehension of logical quantifiers (e.g. “Some of the birds are on the branch”), associated with a simple form of perceptual logic, and this correlated with their deficit on executive measures. This deficit was related to disease in rostral prefrontal cortex in bvFTD. These patients were also impaired in their comprehension of majority quantifiers (e.g. “At least half of the birds are on the branch”), and this too was correlated with their deficit on executive measures. This was related to disease in the basal ganglia interrupting a frontal–striatal loop critical for executive functioning. These findings suggest that a large-scale frontal–parietal neural network plays a crucial role in quantifier comprehension, and that comprehension of specific classes of quantifiers may be selectively impaired in patients with focal neurodegenerative conditions in these areas.

Differential Dynamics of Activity Changes in Dorsolateral and Dorsomedial Striatal Loops during Learning

The basal ganglia are implicated in a remarkable range of functions influencing emotion and cognition as well as motor behavior. Current models of basal ganglia function hypothesize that parallel limbic, associative, and motor cortico-basal ganglia loops contribute to this diverse set of functions, but little is yet known about how these loops operate and how their activities evolve during learning. To address these issues, we recorded simultaneously in sensorimotor and associative regions of the striatum as rats learned different versions of a conditional T-maze task. We found highly contrasting patterns of activity in these regions during task performance and found that these different patterns of structured activity developed concurrently, but with sharply different dynamics. Based on the region-specific dynamics of these patterns across learning, we suggest a working model whereby dorsomedial associative loops can modulate the access of dorsolateral sensorimotor loops to the control of action.

Accumbens core-shell dichotomy and beyond: 25 years of progress

Event Abstract Back to Event Accumbens core-shell dichotomy and beyond: 25 years of progress László Záborszky1* 1 Rutgers University, Center for Molecular and Behavioral Neuroscience, United States The discovery that the dorsal striatum and globus pallidus extend ventrally underneath the anterior commissure into the substantia innominata lead to the realization that the entire cortical mantle projects to the basal ganglia (Heimer et al., 1982). This ventral cortical-striatal-pallidal system via the medio-dorsal thalamic nucleus back to the prefrontal cortex represented one of the earliest anatomical concepts of the segregated cortical-subcortical reentrant circuits through the basal ganglia to influence the motor and prefrontal cortices as suggested by functional studies for the classical dorsal motor-related cortico-striatal-pallidal systems (DeLong and Georgopoulos, 1981; Alexander et al., 1986). This was a paradigm shift from the classical limbic-versus-basal ganglia dichotomy as dominated textbooks of that time. These parallel, re-entrant macrocircuits have been suggested to participate in different global functions, whereas a ventromedial prefrontal–ventral striatal loop mediate motivational and reward processing, more dorsal loops engage in sensorimotor or cognitive processing (Alexander et al., 1990). Information processed along these pathways is under the modulatory control of dopamine released from axons originating in the ventral tegmental area and substantia nigra pars compacta. A new parcellation of the nucleus accumbens (a centrally located core and a peripheral, ventrally located shell: Zaborszky et al., 1985); refined connectional studies in basal ganglia circuitry (Groenewegen), advances in learning theory (Dickinson) and detailed pharmaco-behavioral studies (Robbins, Everitt, Berridge, Kelley) began to shed light how psychological functions, including goal directed actions and habits are mapped onto actual anatomical forebrain circuitries via the n. accumbens core and shell. Since goal-directed behavior in these circuitries are triggered by natural reinforcer (food) or drugs of abuse, these psychobiological studies –that are firmly based in anatomical studies and conceptualizations, could lead to rational therapeutic strategies to cure drug addiction. Supported by NIH Grant NS023945. Conference: IBRO International Workshop 2010, Pécs, Hungary, 21 Jan - 23 Jan, 2010. Presentation Type: Oral Presentation Topic: Neural mechanisms of the basal ganglia and ventrobasal forebrain Citation: Záborszky L (2010). Accumbens core-shell dichotomy and beyond: 25 years of progress. Front. Neurosci. Conference Abstract: IBRO International Workshop 2010. doi: 10.3389/conf.fnins.2010.10.00237 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 05 May 2010; Published Online: 05 May 2010. * Correspondence: László Záborszky, Rutgers University, Center for Molecular and Behavioral Neuroscience, Newark, United States, zaborszky@axon.rutgers.edu Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers László Záborszky Google László Záborszky Google Scholar László Záborszky PubMed László Záborszky Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

A study on cognitive flexibility in hepatic type hepatolenticular degeneration patients

Objective To assess the characteristics of cognition flexibility in hepatic type hepatolenticular degeneration(HLD) patients through neuropsychological tests;and to research on the mechanism of cognition flexibility dysfunction in hepatic type HLD patients. Methods 36 hepatic type patients were researched as HLD group. 30 healthy people were selected as control group. All the patients and control group were recorded the sex, age, years of education and the test results of Raven's standard progressive matrices (R'SPM), trail making test (TMT). Results HLD group compared with control group were exceedingly significantly difference in A item time-consuming [(35.94±11.51)s],B item time-consuming [(117.94±44.30)s] and interference effects (82.42±43.49) of TMT ( P <0.05 or P <0.01). It were significantly different in intelligence quotient,similar comparison,abstract inference items of R'SPM( P <0.05). The B item time-consuming and interference effects of TMT were correlated positively to age, course of disease in HLD group( P <0.05 or P <0.01).The scores of comparative inference of R'SPM were correlated negatively to age, course of disease in HLD group ( P <0.05). Conclusion Cognitive flexibility dysfunction were appearing in hepatic type HLD patients. Damages of frontal - striatal loop functions caused to minimal hepatic encephalopathy were capital mechanisms of cognitive flexibility dysfunction in hepatic type HLD patients. Key words: Hepatolenticular degeneration; Cognitive flexibility; Minimal hepatic encephalopathy

Differential frontal–striatal and paralimbic activity during reversal learning in major depressive disorder and obsessive–compulsive disorder

Several lines of research suggest a disturbance of reversal learning (reward and punishment processing, and affective switching) in patients with major depressive disorder (MDD). Obsessive-compulsive disorder (OCD) is also characterized by abnormal reversal learning, and is often co-morbid with MDD. However, neurobiological distinctions between the disorders are unclear. Functional neuroimaging (activation) studies comparing MDD and OCD directly are lacking. Twenty non-medicated OCD-free patients with MDD, 20 non-medicated MDD-free patients with OCD, and 27 healthy controls performed a self-paced reversal learning task in an event-related design during functional magnetic resonance imaging (fMRI). Compared with healthy controls, both MDD and OCD patients displayed prolonged mean reaction times (RTs) but normal accuracy. In MDD subjects, mean RTs were correlated with disease severity. Imaging results showed MDD-specific hyperactivity in the anterior insula during punishment processing and in the putamen during reward processing. Moreover, blood oxygen level-dependent (BOLD) responses in the dorsolateral prefrontal cortex (DLPFC) and the anterior PFC during affective switching showed a linear decrease across controls, MDD and OCD. Finally, the OCD group showed blunted responsiveness of the orbitofrontal (OFC)-striatal loop during reward, and in the OFC and anterior insula during affective switching. This study shows frontal-striatal and (para)limbic functional abnormalities during reversal learning in MDD, in the context of generic psychomotor slowing. These data converge with currently influential models on the neuropathophysiology of MDD. Moreover, this study reports differential neural patterns in frontal-striatal and paralimbic structures on this task between MDD and OCD, confirming previous findings regarding the neural correlates of deficient reversal learning in OCD.

α2A-Adrenoceptors Strengthen Working Memory Networks by Inhibiting cAMP-HCN Channel Signaling in Prefrontal Cortex

Spatial working memory (WM; i.e., "scratchpad" memory) is constantly updated to guide behavior based on representational knowledge of spatial position. It is maintained by spatially tuned, recurrent excitation within networks of prefrontal cortical (PFC) neurons, evident during delay periods in WM tasks. Stimulation of postsynaptic alpha2A adrenoceptors (alpha2A-ARs) is critical for WM. We report that alpha2A-AR stimulation strengthens WM through inhibition of cAMP, closing Hyperpolarization-activated Cyclic Nucleotide-gated (HCN) channels and strengthening the functional connectivity of PFC networks. Ultrastructurally, HCN channels and alpha2A-ARs were colocalized in dendritic spines in PFC. In electrophysiological studies, either alpha2A-AR stimulation, cAMP inhibition or HCN channel blockade enhanced spatially tuned delay-related firing of PFC neurons. Conversely, delay-related network firing collapsed under conditions of excessive cAMP. In behavioral studies, either blockade or knockdown of HCN1 channels in PFC improved WM performance. These data reveal a powerful mechanism for rapidly altering the strength of WM networks in PFC.

Effects of levodopa and subthalamic nucleus stimulation on cognitive and affective functioning in Parkinson's disease

In Parkinson's disease (PD), levodopa and subthalamic nucleus (STN) stimulation lead to major improvement in motor symptoms. Effects of both treatments on cognition and affective status are less well understood. Motor, cognitive, and affective symptoms may relate to the dysfunctioning of parallel cortico-striatal loops. The aim of this study was to assess cognition, behavior, and mood, with and without both treatments in the same group of PD patients. A group of 22 nondemented PD patients was included in this study. Patients were tested twice before surgery (off and on levodopa) and twice 3 months after surgery (OFF and ON STN stimulation, off levodopa). Cognitive and affective effects of STN stimulation and levodopa had some common, but also different, effects. STN stimulation improved performance on the planning test, associated with the dorsolateral prefrontal cortex. However, the treatments had opposite effects on tests associated with the orbitofrontal cortex; specifically, levodopa impaired while STN stimulation improved performance on the extinction phase of a reversal/extinction task. Acutely, both treatments improved motivation and decreased fatigue and anxiety. On chronic treatment (3 months after surgery), depression improved, whereas apathy worsened 3 months after surgery. To conclude, there were significant but contrasting effects of levodopa and STN stimulation on cognition and affective functions.

Obsessive-compulsive disorder and executive deficits in two patients with primary dystonia

In spite of the high prevalence of behavioral and cognitive disturbances found in most basal ganglia disorders and attributed to fronto-striatal dysfunction, the existence of psychiatric and cognitive symptoms in patients with primary dystonia remains controversial. We present a 42-year-old female with primary writer's cramp and obsessive-compulsive disorder (OCD) and a 59-year-old male with Meigs syndrome, idiopathic torticollis and OCD. Both patients had mild executive dysfunction. The coexistence of psychiatric, cognitive and motor symptoms of different intensity may be explained by variable dysfunction on different frontal–striatal loops, as proposed by the open interconnected model of fronto-striatal circuits.

Evolution of Alzheimer's disease related cortical lesions.

Alzheimer's disease is an immutably progressing dementing disorder. Its major pathologic hallmark is the gradual development of neurofibrillary changes in a few susceptible nerve cell types. The cortical changes do not occur inevitably with advancing age. Once the disease has begun, spontaneous recovery or remissions are not observed. The initial changes develop in poorly myelinated areas of the temporal lobe. The destructive process then follows a predictable pattern as it extends into other cortical areas. Advanced age is not a prerequisite for the evolution of the lesions. Alzheimer's disease is thus an age-related, but not an age-dependent disease. The spread of the neurofibrillary changes resembles the process of cortical myelination, however in reverse order.

Basal ganglia: functional anatomy and physiology. Part 2.

Advances in knowledge about basal ganglia function and circuitry are reviewed. Despite the voluminous available literature on this subject, the role of basal ganglia in health and disease remains controversial. Experimental data on the effects of stimulation and ablation of the basal ganglia are summarized. The roles of the basal ganglia in the preparation for and execution of cortically initiated movement are described. Newer roles ascribed to the basal ganglia in sensory-motor gating, cognition, emotion, and motivation are discussed. The old and current concepts of information flow between the cerebral cortex, striatum, pallidum, thalamus, and back to the cerebral cortex are reviewed. The "funnel" system of information flow has been discarded in favor of several parallel and largely segregated loops pertaining to motor, oculomotor, cognitive, and limbic functions. The anatomic substrate of each of these loops is described. The specific roles of the striatum, pallidum, substantia nigra, and thalamus in information flow as related to movement are described. The roles of the basal ganglia in reinforcing wanted behavior and suppressing unwanted behavior via direct and indirect striatal loops are discussed. The implications of these loops in the genesis of Parkinson's disease and Huntington's chorea are described. Alteration in basal ganglia neurotransmitters and neuromodulators in Huntington's chorea, Tourette's syndrome, and Parkinson's disease are described.