[Transfer of autologous fat and plasma : The future of anti-aging medicine?]. / Autologer Fett- und Bluttransfer : Die Zukunft der Anti-aging-Medizin?

BACKGROUND: Aging is a complex process driven by endogenous and exogenous stimuli. The distinct cellular and noncellular components of skin and adjacent connective tissue are constantly and irreversibly degraded during aging. OBJECTIVES: The aim was to provide an overview of the biology of skin aging and the therapeutic options for rejuvenation. METHODS: A review of the current literature and a demonstration of autologous fat transfer and platelet-rich plasma (PRP) are presented from a clinical perspective. RESULTS: The aging process affects cellular components and the extracellular matrix (ECM); thus, the first stage is the degradation of the ECM. The loss of skin elasticity is induced by a breakdown of fibers such as collagen, elastin, or reticulin, whereas the degradation of proteoglycans results in decreased turgor and skin hydration. Synthetic filling agents primarily compensate for volume loss, but do not rejuvenate biologically. In contrast, the transfer of autologous fat and PRP is based on activating stem cell populations and growth factors, in addition to providing volume to target regions. CONCLUSIONS: A profound comprehension of the cellular and molecular mechanisms of aging is important in anti-aging medicine. The transfer of autologous fat and PRP offers interesting alternatives in the sense of more biological skin rejuvenation.

Differential role of visuospatial working memory in the propensity toward uncertainty in patients with obsessive-compulsive disorder and in healthy subjects.

BACKGROUND: Obsessive-compulsive disorder (OCD) is associated with visuospatial working memory deficits. Intolerance of uncertainty is thought to be a core component of OCD symptoms. Recent findings argue for a possible relationship between abilities in visuospatial memory and uncertainty. However, this relationship remains unclear in both OCD patients and healthy subjects. To address this issue, we measured performance in visuospatial working memory and the propensity to express uncertainty during decision making. We assessed their relationship and the temporal direction of this relationship in both OCD patients and healthy subjects. METHOD: Baseline abilities in visuospatial working memory were measured with the Corsi block-tapping test. A delayed matching-to-sample task was used to identify explicit situations of certainty, uncertainty and ignorance and to assess continuous performance in visuospatial working memory. Behavioural variables were recorded over 360 consecutive trials in both groups. RESULTS: Baseline scores of visuospatial working memory did not predict the number of uncertain situations in OCD patients whereas they did in healthy subjects. Uncertain trials led to reduced abilities in visuospatial working memory to 65% of usual performance in OCD patients whereas they remained stable in healthy subjects. CONCLUSIONS: The present findings show an opposite temporal direction in the relationship between abilities in working memory and uncertainty in OCD patients and healthy subjects. Poor working memory performance contributes to the propensity to feel uncertainty in healthy subjects whereas uncertainty contributes to decreased continuous performance in working memory in OCD patients.

Evolution of brain gray matter loss in Huntington's disease: a meta-analysis.

BACKGROUND: Huntington's disease is characterized by neuronal loss throughout the disease course. Voxel-based morphometry studies have reported reductions in gray matter concentration (GMC) in many brain regions in patients with Huntington. The description of the time course of gray matter loss may help to identify some evolution markers. Here, we conducted a meta-analysis of voxel-based morphometry studies of Huntington's disease to describe the evolution of brain gray matter loss. METHODS: A systematic search led to the inclusion of 11 articles on Huntington's disease (297 patients and 205 controls). We extracted data from patients with preclinical Huntington, patients with clinical Huntington, and controls. Finally, anatomical likelihood estimation analyses were conducted to identify GMC changes between preclinical patients and controls, between clinical patients and controls, and between preclinical and clinical patients. RESULTS: Preclinical patients exhibited gray matter loss in the left basal ganglia and the prefrontal cortex. Clinical patients had bilateral gray matter loss in the basal ganglia, the prefrontal cortex, and the insula. The left striatum was smaller in clinical patients than in preclinical patients. CONCLUSIONS: Neurodegenerative processes associated with Huntington's disease, as assessed by GMC reduction, begin in the left hemisphere and extend to the contralateral hemisphere throughout the inexorable course of the disease. Changes in gray matter, especially the volumetric side ratio of the striatum, could represent a relevant biomarker for characterizing the different progression stages of the disease.

The associative and limbic thalamus in the pathophysiology of obsessive-compulsive disorder: an experimental study in the monkey.

Obsessive-compulsive disorder (OCD) is a frequent psychiatric disorder characterized by repetitive intrusive thoughts and severe anxiety, leading to compulsive behaviors. Although medical treatment is effective in most cases, resistance is observed in about 30% of patients. In this context, deep brain stimulation (DBS) of the caudate or subthalamic nuclei has been recently proposed with encouraging results. However, some patients were unimproved or exhibited awkward side effects. Therefore, exploration of new targets for DBS remains critical in OCD. In the latter, functional imaging studies revealed overactivity in the limbic and associative cortico-subcortical loops encompassing the thalamus. However, the role of the thalamus in the genesis of repetitive behaviors and related anxiety is unknown. Here, we tested the hypothesis that pharmacological-induced overactivity of the medial thalamus could give rise to abnormal behaviors close to that observed in OCD. We modulated the ventral anterior (VA) and medial dorsal (MD) nuclei activity by in situ bicuculline (GABA(A) antagonist) microinjections in subhuman primates and assessed their pharmacological-induced behavior. Bicuculline injections within the VA caused significant repetitive and time-consuming motor acts whereas those performed within the MD induced symptoms of dysautonomic dysregulation along with abnormal vocalizations and marked motor hypoactivity. These findings suggest that overactivation of the VA and MD nuclei of the thalamus provokes compulsive-like behaviors and neurovegetative manifestations usually associated with the feeling of anxiety in OCD patients. In further research, this translational approach should allow us to test the effectiveness and side effects of these thalamic nuclei DBS in monkey and perhaps, in a second step, to propose a transfer of this technique to severely disabled OCD patients.

Oscillatory entrainment of subthalamic nucleus neurons and behavioural consequences in rodents and primates.

We investigated the functional role of oscillatory activity in the local field potential (LFP) of the subthalamic nucleus (STN) in the pathophysiology of Parkinson's disease (PD). It has been postulated that beta (15-30 Hz) oscillatory activity in the basal ganglia induces PD motor symptoms. To assess this hypothesis, an LFP showing significant power in the beta frequency range (23 Hz) was used as a stimulus both in vitro and in vivo. We first demonstrated in rat brain slices that STN neuronal activity was driven by the LFP stimulation. We then applied beta stimulation to the STN of 16 rats and two monkeys while quantifying motor behaviour. Although stimulation-induced behavioural effects were observed, stimulation of the STN at 23 Hz induced no significant decrease in motor performance in either rodents or primates. This study is the first to show LFP-induced behaviour in both rats and primates, and highlights the complex relationship between beta power and parkinsonian symptoms.

Subthalamic nucleus evokes similar long lasting glutamatergic excitations in pallidal, entopeduncular and nigral neurons in the basal ganglia slice.

The subthalamic nucleus (STN) modulates the activity of globus pallidus (GP), entopeduncular nucleus (EP) and substantia nigra pars reticulata (SNr) neurons via its direct glutamatergic projections. To investigate the mechanism by which STN affects activity in these structures and whether STN induced activity is comparable among STN target neurons, we performed patch clamp recordings in a tilted, parasagittal, basal ganglia slice (BGS) that preserves these functional connections. We report that single, brief stimulation of the STN generates a brief monosynaptic AMPA-mediated excitatory postsynaptic current (EPSC) in GP, EP and SNr neurons. A higher intensity, supra-threshold activation evokes a compound EPSC consisting of an early monosynaptic component followed by a slow inward NMDA-mediated current with an overlying barrage of AMPA-mediated EPSCs. These late EPSCs were polysynaptic and gave rise to bursts of spikes that lasted several hundreds of milliseconds. They were eliminated by surgical removal of the STN from the BGS slice, indicating that the STN is required for their generation. Reconstruction of biocytin-filled STN neurons revealed that a third of STN neurons project intra-STN axon collaterals that may underlie polysynaptic activity. We propose that activation of the STN yields comparable long lasting excitations in its target neurons by means of a polysynaptic network.

The glutamate-based genetic immune hypothesis in obsessive-compulsive disorder. An integrative approach from genes to symptoms.

Recent advances in multiple areas of research have contributed to the identification of several pathophysiological factors underlying obsessive-compulsive disorder (OCD). In particular, the glutamate transporter gene SLC1A1 has been associated with the diagnosis of OCD. Immunological and infectious studies have reported alterations of the immune system and the presence of immune complexes directed against the Borna disease virus in OCD patients. In addition, neuroimaging of OCD patients has demonstrated abnormalities in the anterior cingulate cortex, orbitofrontal cortex, thalamus, and the basal ganglia. Neuropsychological assessments have found several cognitive disruptions that have been identified in OCD, especially impairments in cognitive flexibility. Here, we attempt to bridge the gap between these remarkable findings through several previously unpredicted pathophysiological mechanisms. We propose an integrative hypothesis that indicates how genetic and environmental factors may contribute to the structural and functional alterations of cortico-subcortical circuits, leading to the characteristic cognitive disruptions underlying OCD symptoms.

Is there a link between alertness and fatigue in patients with traumatic brain injury?

OBJECTIVES: Many patients with traumatic brain injury (TBI) report chronic fatigue, and previous studies showed a potential relationship between sleepiness and fatigue in these patients. Our study first looked at the impact of objective and subjective sleepiness on fatigue in patients with TBI. We then investigated how fatigue could affect driving performance in these patients. METHODS: Nocturnal polysomnography, the Fatigue Severity Scale (FSS), the Epworth Sleepiness Scale (ESS), and five 40-minute maintenance of wakefulness tests (MWT) were collected in 36 patients with TBI. Fitness to drive was assessed in a subsample of 22 patients compared to 22 matched controls during an hour simulated driving session. RESULTS: In patients with TBI, FSS, ESS, and mean MWT scores (+/-SD) were 27 +/- 10, 8 +/- 4, and 35 +/- 7 minutes vs 15 +/- 2.5, 5 +/- 3, and 37 +/- 5 minutes in controls. Patients with TBI reported more chronic fatigue (W = 99, p < 0.001) than controls, and, unlike in controls, the level of chronic fatigue was correlated to their MWT scores. Patients' driving performances were worse than the controls' (W = 79, p < 0.001). The best predictive factors of driving performance were fatigue scores and body mass index (multiple R = 0.458, 41.8% of explained variance). CONCLUSION: In patients with TBI, chronic fatigue is significantly related to subjective and objective levels of alertness, even though these levels are not highly pathologic. This might suggest that a small level of sleepiness (i.e., MWT scores between 33 and 39 minutes) worsens fatigue in these patients. Chronic fatigue and body mass index could predict driving simulator performance in patients with TBI.

Differential behavioral effects of partial bilateral lesions of ventral tegmental area or substantia nigra pars compacta in rats.

Akinesia (or absence of movement) is a prominent feature of Parkinson's disease. Akinetic symptoms, however, are also observed in depression and schizophrenia, which support the hypothesis that akinesia involves more than only motor behavior. A common feature of these disorders is the disruption of dopamine homeostasis in the CNS. Here we aimed at relating the respective involvement of the nigrostriatal and mesocortical dopaminergic pathways to akinesia. We investigated in the rat the relative effects of selective bilateral partial lesions of substantia nigra pars compacta (SNc) or ventral tegmental area (VTA) which did not affect locomotion, on fine motor, motivational and cognitive behaviors. Motor impairments were measured by the evaluation of fine motor control in the stepping test and in the paw reaching test. Cognitive functions were assessed by various paradigms: spontaneous alternation in the Y maze and object exploration task. Motivational behavior was evaluated by the 100-pellets test. The results suggested that specific behavioral impairments are obtained following selective lesions of either SNc or VTA. SNc-lesioned rats exhibited deficits in fine motor functions as previously described in animal models of Parkinson's disease, whereas VTA-lesioned rats demonstrated traits of perseveration without significant motor impairments.

Sensory motor mismatch within the supplementary motor area in the dystonic monkey.

Dystonia, a movement disorder characterized by abnormal postures, is associated in primary forms of the disease with subtle proprioceptive troubles and aberrant somatotopic representation in the somatosensory cortex (SC). However, it is unclear whether these sensory features are a causal phenomenon or a consequence of dystonia. The supplementary motor area proper (SMAp), a premotor cortical region, receives strong inputs from both the SC and basal ganglia. We hypothesized that disruption in sensory-motor integration within the SMAp may play a part in the pathophysiology of dystonia. Using a model of secondary dystonia obtained by 3-nitropropionic acid intoxication in rhesus monkeys, we first provide evidence that the SMAp was overexcitable in dystonic animals. Second, we show that proprioceptive inputs processed by SMAp neurons were dramatically increased with wider sensory receptive fields and a mismatch between sensory inputs and motor outputs. These findings suggest that abnormal sensory inputs impinging upon SMAp neurons play a critical role in the pathophysiology of dystonia.

A challenging task for assessment of checking behaviors in obsessive-compulsive disorder.

OBJECTIVE: The present study concerns the objective and quantitative measurement of checking activity, which represents the most frequently observed compulsions in obsessive-compulsive disorder (OCD). To address this issue, we developed an instrumental task producing repetitive checking in OCD subjects. METHOD: Fifty OCD subjects and 50 normal volunteers (NV) were administered a delayed matching-to-sample task that offered the unrestricted opportunity to verify the choice made. Response accuracy, number of verifications, and response time for choice taken to reflect the degree of uncertainty and doubt were recorded over 50 consecutive trials. RESULTS: Despite similar levels of performance, patients with OCD demonstrated a greater number of verifications and a longer response time for choice before checking than NV. Such behavioral patterns were more pronounced in OCD subjects currently experiencing checking compulsions. CONCLUSION: The present task might be of special relevance for the quantitative assessment of checking behaviors and for determining relationships with cognitive processes.

[Present contribution of neurosciences to a new clinical reading of obsessive-compulsive disorder]. / Apport actuel des neurosciences à travers une nouvelle lecture clinique du trouble obsessionnel compulsif.

Obsessive-compulsive disorder (OCD), that affects 2 to 3% of the general population, is characterized by recurrent intrusive thoughts and repetitive, time-consuming behaviors. It is a severely incapacitating mental illness that causes profound impairment in psychosocial functioning and quality of life. Although the physiopathology of OCD is still far from resolved, the existence of a biological basis for OCD is now clearly established and should be interpreted from phenomenological considerations, on the one hand, and in the light of our increasing knowledge of the physiology of cortico-subcortical functional loops, on the other. In a phenomenological view, the heart of the obsessional process is the subject's underlying impression that "something is wrong". In other words, obsessions may be thought of as the permanent perception of a mistake and/or error in certain behavioral situations. Compulsions occur as behavioral responses aimed at relieving the tensions or anxiety generated by the situation. If obtained, this relief may be felt to be a form of reward. Nevertheless, it is only transient, thereby creating a feeling of considerable anxiety. This contributes to immediately reproducing the behavior in a cyclic manner, on the basis of an internal motivational state through an expectation of the reward. Therefore, it can be assumed that several malfunctioning processes are altered within the OCD: 1) error recognition; and, 2) emotion and motivation. This suggests that there is a dysfunction of the brain regions mediating these cognitive and emotional functions. Experimental neurophysiology in laboratory animals indicates the central role of the fronto-subcortical circuits originating in the orbitofrontal and anterior cingulate cortices, respectively. The orbitofrontal cortex (OFC) and ventromedial areas are involved in appraisal of the emotional and motivational values of environmental information, and in integrating the subject's prior experience, which is crucial in decision-making. The OFC also contributes to the selection, comparison and judgment of stimuli and error detection. The anterior cingulate cortex (ACC) is comprised of 1) a ventral or affective region that could keep attention on the internal emotional and motivational status and regulation of autonomic responses, and 2) a dorsal and cognitive region that serves a wide range of functions including attention, working memory, error detection, conflict monitoring, response selection, and anticipation of incoming information. Ventral striatum, that is intimately connected to the OFC and ACC, participates in the preparation, initiation and execution of behavioral responses oriented toward reward delivery following the cognitive and emotional integration of behaviorally relevant information at the cortical level. Functional imaging research in humans has shown an increased functional activity in the OFC, ACC, head of the caudate nucleus and thalamus in OCD patients. These functional abnormalities have been found in basal conditions and during provocation tests. Moreover, the therapeutic efficacy of antidepressants with preponderant serotonin-reuptake inhibiting properties and cognitive-behavioral therapies seems to be associated with a progressive reduction in activity of the OFC, ACC and the caudate nucleus. Therefore, these observations are suggestive of the responsibility of 5HT neurotransmission in the dysfunction of the frontal-subcortical loops that emanate from the OFC and ACC. However, several lines of research suggest that the dopamine system, with which 5HT interacts, may play a major role in the expression of OC symptoms. In conclusion, it seems that in OCD there is a dysfunction of the brain regions that belong to the orbitofrontal and anterior cingulate loops in view of evidence obtained from separate and complementary approaches.

Side-effects of subthalamic stimulation in Parkinson's disease: clinical evolution and predictive factors.

Chronic bilateral high-frequency stimulation of the subthalamic nucleus (STN) is an alternative treatment for disabling forms of Parkinson's disease when on-off fluctuations and levodopa-induced dyskinesias compromise patients' quality of life. The aim of this study was to assess the evolution of side-effects during the first year of follow-up and search for clinical predictive factors accounting for their occurrence. We compared the frequency of side-effects at 3 and 12 months after surgery in a cohort of 44 patients. The off-medication scores of Unified Parkinson's Disease Rating Scale (UPDRS) II, III, axial symptoms, disease duration and age at surgery were retained for correlation analysis. Dysarthria/hypophonia, weight gain and postural instability were the most frequent chronic side-effects. Whereas dysarthria/hypophonia remained stable over time, weight gain and postural instability increased during the first year post-op. High axial and UPDRS II scores at surgery were predictive of dysarthria/hypophonia. Age and axial score at surgery were positively correlated with postural instability. Despite the occurrence of side-effects, the benefit/side-effects ratio of STN stimulation was largely positive during the first year of follow-up. Age, intensity of axial symptoms and UDPRS II off-medication score before surgery are predictive factors of dysarthria/hypophonia and postural instability after surgery.

Clinical and economic results of bilateral subthalamic nucleus stimulation in Parkinson's disease.

BACKGROUND: High frequency stimulation of the subthalamic nucleus (STN) is an alternative but expensive neurosurgical treatment for parkinsonian patients with levodopa induced motor complications. OBJECTIVE: To assess the safety, clinical effects, quality of life, and economic cost of STN stimulation. METHODS: We conducted a prospective multicentre study in 95 consecutive Parkinson's disease (PD) patients receiving bilateral STN stimulation and assessed its effects over 12 months. A double blind randomised motor evaluation was carried out at 3 month follow up, and quality of life, self care ability, and predictive factors of outcome following surgery were assessed. The cost of PD was estimated over 6 months before and after surgery. RESULTS: The Unified Parkinson's Disease Rating Scale (UPDRS) motor score improved by 57% (p<0.0001) and activities of daily living improved by 48% (p<0.0001) at 12 month follow up. Double blind motor scoring improved by 51% at 3 month follow up (p<0.0001). The total PD Quality of Life Questionnaire (PDQL-37) score improved by 28% (p<0.001). The better the preoperative motor score after a levodopa challenge, the better the outcome after STN stimulation. Five patients developed an intracerebral haematoma during electrode implantation with permanent after effects in two. The 6 month costs of PD decreased from 10,087 euros before surgery to 1673 euros after surgery (p<0.0001) mainly because of the decrease in medication. These savings allowed a return on the procedure investment, estimated at 36,904 euros over 2.2 years. CONCLUSIONS: STN stimulation has good outcomes with relatively low risk and little cost burden in PD patients with levodopa induced motor complications.

Evolution of postural stability after subthalamic nucleus stimulation in Parkinson's disease: a combined clinical and posturometric study.

OBJECTIVES: The occurrence of postural and balance disorders is a frequent feature in advanced forms of Parkinson's disease (PD). However, the pathological substrate of these disturbances is poorly understood. METHODS: In the present work, we investigated the evolution of posturometric parameters [center of pressure (CoP) displacement and CoP area] and axial scores between the pre-operative period and 3 months post-operative in seven PD patients who underwent bilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN). RESULTS: After surgery, the patients leaned backwards much more regardless of the STN stimulation, suggesting that surgery could have a deleterious effect on postural adaptation. During the post-operative period, the improvement in axial and postural scores was similar under levodopatherapy and DBS. On the other hand, DBS of the STN significantly reduced the CoP displacement and the CoP area, whereas levodopatherapy tended only to reduce the CoP displacement and to increase the CoP area significantly. CONCLUSIONS: These data suggest that DBS of the STN and levodopa do not act on the same neurological systems involved in posture regulation. DBS of the STN could improve posture via a direct effect on the pedunculopontine nucleus, which is known to be involved in posture regulation.

[Animal models of parkinsonism]. / Modèles animaux des syndromes parkinsoniens.

Research into the pathophysiology of Parkinson's disease has been rapidly advanced by the development of animal models. Initial models were developed by using toxins that specifically targeted dopamine neurons, the most successful of which used 6-hydroxydopamine in rats and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice and primates. Their combination with specific striatal toxins, such as quinolinic acid or 3-nitropropionic acid, has led to the development of experimental models replicating the salient pathological and clinical features of multiple system atrophy of the striatonigral degeneration subtype both in rodents and primates. More recently, the identification of alpha-synuclein gene mutations in rare familial cases of Parkinson's disease has led to the development of alpha-synuclein knock-out and transgenic animals. We conclude that the use and improvement of both phenotypic and genetic models can significantly speed progress toward understanding the pathophysiology of these devastating diseases and finding innovative cures.

Dopamine receptors set the pattern of activity generated in subthalamic neurons.

Information processing in the brain requires adequate background neuronal activity. As Parkinson's disease progresses, patients typically become akinetic; the death of dopaminergic neurons leads to a dopamine-depleted state, which disrupts information processing related to movement in a brain area called the basal ganglia. Using agonists of dopamine receptors in the D1 and D2 families on rat brain slices, we show that dopamine receptors in these two families govern the firing pattern of neurons in the subthalamic nucleus, a crucial part of the basal ganglia. We propose a conceptual frame, based on specific properties of dopamine receptors, to account for the dominance of different background firing patterns in normal and dopamine-depleted states.

The restless legs syndrome.

The restless legs syndrome (RLS) is one of the commonest neurological sensorimotor disorders at least in the Western countries and is often associated with periodic limb movements (PLM) during sleep leading to severe insomnia. However, it remains largely underdiagnosed and its underlying pathogenesis is presently unknown. Women are more affected than men and early-onset disease is associated with familial cases. A genetic origin has been suggested but the mode of inheritance is unknown. Secondary causes of RLS may share a common underlying pathophysiology implicating iron deficiency or misuse. The excellent response to dopaminegic drugs points to a central role of dopamine in the pathophysiology of RLS. Iron may also represent a primary factor in the development of RLS, as suggested by recent pathological and brain imaging studies. However, the way dopamine and iron, and probably other compounds, interact to generate the circadian pattern in the occurrence of RLS and PLM symptoms remains unknown. The same is also the case for the level of interaction of the two compounds within the central nervous system (CNS). Recent electrophysiological and animals studies suggest that complex spinal mechanisms are involved in the generation of RLS and PLM symptomatology. Dopamine modulation of spinal reflexes through dopamine D3 receptors was recently highlighted in animal models. The present review suggests that RLS is a complex disorder that may result from a complex dysfunction of interacting neuronal networks at one or several levels of the CNS and involving numerous neurotransmitter systems.