Early and late stimulus-evoked cortical hemodynamic responses provide insight into the neurogenic nature of neurovascular coupling

Understanding neurovascular coupling is a prerequisite for the interpretation of results obtained from modern neuroimaging techniques. This study investigated the hemodynamic and neural responses in rat somatosensory cortex elicited by 16 seconds electrical whisker stimuli. Hemodynamics were measured by optical imaging spectroscopy and neural activity by multichannel electrophysiology. Previous studies have suggested that the whisker-evoked hemodynamic response contains two mechanisms, a transient ‘backwards’ dilation of the middle cerebral artery, followed by an increase in blood volume localized to the site of neural activity. To distinguish between the mechanisms responsible for these aspects of the response, we presented whisker stimuli during normocapnia (‘control’), and during a high level of hypercapnia. Hypercapnia was used to ‘predilate’ arteries and thus possibly ‘inhibit’ aspects of the response related to the ‘early’ mechanism. Indeed, hemodynamic data suggested that the transient stimulus-evoked response was absent under hypercapnia. However, evoked neural responses were also altered during hypercapnia and convolution of the neural responses from both the normocapnic and hypercapnic conditions with a canonical impulse response function, suggested that neurovascular coupling was similar in both conditions. Although data did not clearly dissociate early and late vascular responses, they suggest that the neurovascular coupling relationship is neurogenic in origin.

The resting-state neurovascular coupling relationship: rapid changes in spontaneous neural activity in the somatosensory cortex are associated with haemodynamic fluctuations that resemble stimulus-evoked haemodynamics

Although promise exists for patterns of resting-state blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) brain connectivity to be used as biomarkers of early brain pathology, a full understanding of the nature of the relationship between neural activity and spontaneous fMRI BOLD fluctuations is required before such data can be correctly interpreted. To investigate this issue, we combined electrophysiological recordings of rapid changes in multi-laminar local field potentials from the somatosensory cortex of anaesthetized rats with concurrent two-dimensional optical imaging spectroscopy measurements of resting-state haemodynamics that underlie fluctuations in the BOLD fMRI signal. After neural ‘events’ were identified, their time points served to indicate the start of an epoch in the accompanying haemodynamic fluctuations. Multiple epochs for both neural ‘events’ and the accompanying haemodynamic fluctuations were averaged. We found that the averaged epochs of resting-state haemodynamic fluctuations taken after neural ‘events’ closely resembled the temporal profile of stimulus-evoked cortical haemodynamics. Furthermore, we were able to demonstrate that averaged epochs of resting-state haemodynamic fluctuations resembling the temporal profile of stimulus-evoked haemodynamics could also be found after peaks in neural activity filtered into specific electroencephalographic frequency bands (theta, alpha, beta, and gamma). This technique allows investigation of resting-state neurovascular coupling using methodologies that are directly comparable to that developed for investigating stimulus-evoked neurovascular responses.

Oxidised low-density lipoproteins induce rapid platelet activation and shape change through tyrosine kinase and Rho kinase-signaling pathways

Oxidized low-density lipoproteins (oxLDL) generated in the hyperlipidemic state may contribute to unregulated platelet activation during thrombosis. Although the ability of oxLDL to activate platelets is established, the underlying signaling mechanisms remain obscure. Weshow that oxLDL stimulate platelet activation through phosphorylation of the regulatory light chains of the contractile protein myosin IIa (MLC). oxLDL, but not native LDL, induced shape change, spreading, and phosphorylation of MLC (serine 19) through a pathway that was ablated under conditions that blocked CD36 ligation or inhibited Src kinases, suggesting a tyrosine kinase–dependent mechanism. Consistent with this, oxLDL induced tyrosine phosphorylation of a number of proteins including Syk and phospholipase C g2. Inhibition of Syk, Ca21 mobilization, and MLC kinase (MLCK) only partially inhibited MLC phosphorylation, suggesting the presence of a second pathway. oxLDL activated RhoA and RhoA kinase (ROCK) to induce inhibitory phosphorylation of MLC phosphatase (MLCP). Moreover, inhibition of Src kinases prevented the activation of RhoA and ROCK, indicating that oxLDL regulates contractile signaling through a tyrosine kinase–dependent pathway that induces MLC phosphorylation through the dual activation of MLCK and inhibition of MLCP. These data reveal new signaling events downstream of CD36 that are critical in promoting platelet aggregation by oxLDL.

Correlates of early reading comprehension skills: a componential analysis

This study had three main aims. First, we examined to what extent listening comprehension, vocabulary, grammatical skills and verbal short-term memory (VSTM) assessed prior to formal reading instruction explained individual differences in early reading comprehension levels. Second, we examined to what extent the three common component skills, namely vocabulary, grammar and VSTM explained the relationship between kindergarten listening comprehension and early reading comprehension levels. Third, we examined the relative contributions of word-reading and listening comprehension skills to early reading comprehension in Turkish. For this purpose, 56 Turkish-speaking children were followed from kindergarten (mean age = 67.7 months) into Grade 2 (mean age = 90.6 months). The relative role of kindergarten listening comprehension, vocabulary, VSTM and grammatical skills in later reading comprehension tended to vary across time, and they partly explained the relationship between listening comprehension and reading comprehension. Finally, as anticipated, listening comprehension, rather than word-reading , was found to play a more powerful role in children’s reading comprehension levels even during the early primary grades. These results contradicted those reported in English and can be explained by the rapid development of accurate word-reading skills due to the consistency of the grapheme–phoneme relationships of the Turkish orthography.

Minor structural abnormalities in the infant face disrupt neural processing: a unique window into early caregiving responses

Infant faces elicit early, specific activity in the orbitofrontal cortex (OFC), a key cortical region for reward and affective processing. A test of the causal relationship between infant facial configuration and OFC activity is provided by naturally occurring disruptions to the face structure. One such disruption is cleft lip, a small change to one facial feature, shown to disrupt parenting. Using magnetoencephalography, we investigated neural responses to infant faces with cleft lip compared with typical infant and adult faces. We found activity in the right OFC at 140 ms in response to typical infant faces but diminished activity to infant faces with cleft lip or adult faces. Activity in the right fusiform face area was of similar magnitude for typical adult and infant faces but was significantly lower for infant faces with cleft lip. This is the first evidence that a minor change to the infant face can disrupt neural activity potentially implicated in caregiving.

Effects of action observation on corticospinal excitability: muscle specificity, direction, and timing of the mirror response

Many human behaviours and pathologies have been attributed to the putative mirror neuron system, a neural system that is active during both the observation and execution of actions. While there are now a very large number of papers on the mirror neuron system, variations in the methods and analyses employed by researchers mean that the basic characteristics of the mirror response are not clear. This review focuses on three important aspects of the mirror response, as measured by modulations in corticospinal excitability: (1) muscle specificity, (2) direction, and (3) timing of modulation. We focus mainly on electromyographic (EMG) data gathered following single-pulse transcranial magnetic stimulation (TMS), because this method provides precise information regarding these three aspects of the response. Data from paired-pulse TMS paradigms and peripheral nerve stimulation (PNS) are also considered when we discuss the possible mechanisms underlying the mirror response. In this systematic review of the literature, we examine the findings of 85 TMS and PNS studies of the human mirror response, and consider the limitations and advantages of the different methodological approaches these have adopted in relation to discrepancies between their findings. We conclude by proposing a testable model of how action observation modulates corticospinal excitability in humans. Specifically, we propose that action observation elicits an early, non-specific facilitation of corticospinal excitability (at around 90 ms from action onset), followed by a later modulation of activity specific to the muscles involved in the observed action (from around 200 ms). Testing this model will greatly advance our understanding of the mirror mechanism and provide a more stable grounding on which to base inferences about its role in human behaviour.

Antarctic ocean and sea ice response to ozone depletion: a two timescale problem

The response of the Southern Ocean to a repeating seasonal cycle of ozone loss is studied in two coupled climate models and found to comprise both fast and slow processes. The fast response is similar to the inter-annual signature of the Southern Annular Mode (SAM) on Sea Surface Temperature (SST), on to which the ozone-hole forcing projects in the summer. It comprises enhanced northward Ekman drift inducing negative summertime SST anomalies around Antarctica, earlier sea ice freeze-up the following winter, and northward expansion of the sea ice edge year-round. The enhanced northward Ekman drift, however, results in upwelling of warm waters from below the mixed layer in the region of seasonal sea ice. With sustained bursts of westerly winds induced by ozone-hole depletion, this warming from below eventually dominates over the cooling from anomalous Ekman drift. The resulting slow-timescale response (years to decades) leads to warming of SSTs around Antarctica and ultimately a reduction in sea-ice cover year-round. This two-timescale behavior - rapid cooling followed by slow but persistent warming - is found in the two coupled models analysed, one with an idealized geometry, the other a complex global climate model with realistic geometry. Processes that control the timescale of the transition from cooling to warming, and their uncertainties are described. Finally we discuss the implications of our results for rationalizing previous studies of the effect of the ozone-hole on SST and sea-ice extent. %Interannual variability in the Southern Annular Mode (SAM) and sea ice covary such that an increase and southward shift in the surface westerlies (a positive phase of the SAM) coincides with a cooling of Sea Surface Temperature (SST) around 70-50$^\circ$S and an expansion of the sea ice cover, as seen in observations and models alike. Yet, in modeling studies, the Southern Ocean warms and sea ice extent decreases in response to sustained, multi-decadal positive SAM-like wind anomalies driven by 20th century ozone depletion. Why does the Southern Ocean appear to have disparate responses to SAM-like variability on interannual and multidecadal timescales? Here it is demonstrated that the response of the Southern Ocean to ozone depletion has a fast and a slow response. The fast response is similar to the interannual variability signature of the SAM. It is dominated by an enhanced northward Ekman drift, which transports heat northward and causes negative SST anomalies in summertime, earlier sea ice freeze-up the following winter, and northward expansion of the sea ice edge year round. The enhanced northward Ekman drift causes a region of Ekman divergence around 70-50$^\circ$S, which results in upwelling of warmer waters from below the mixed layer. With sustained westerly wind enhancement in that latitudinal band, the warming due to the anomalous upwelling of warm waters eventually dominates over the cooling from the anomalous Ekman drift. Hence, the slow response ultimately results in a positive SST anomaly and a reduction in the sea ice cover year round. We demonstrate this behavior in two models: one with an idealized geometry and another, more detailed, global climate model. However, the models disagree on the timescale of transition from the fast (cooling) to the slow (warming) response. Processes that controls this transition and their uncertainties are discussed.

Contributions of different cloud types to feedbacks and rapid adjustments in CMIP5

Using five climate model simulations of the response to an abrupt quadrupling of CO2, the authors perform the first simultaneous model intercomparison of cloud feedbacks and rapid radiative adjustments with cloud masking effects removed, partitioned among changes in cloud types and gross cloud properties. Upon CO2 quadrupling, clouds exhibit a rapid reduction in fractional coverage, cloud-top pressure, and optical depth, with each contributing equally to a 1.1 W m−2 net cloud radiative adjustment, primarily from shortwave radiation. Rapid reductions in midlevel clouds and optically thick clouds are important in reducing planetary albedo in every model. As the planet warms, clouds become fewer, higher, and thicker, and global mean net cloud feedback is positive in all but one model and results primarily from increased trapping of longwave radiation. As was true for earlier models, high cloud changes are the largest contributor to intermodel spread in longwave and shortwave cloud feedbacks, but low cloud changes are the largest contributor to the mean and spread in net cloud feedback. The importance of the negative optical depth feedback relative to the amount feedback at high latitudes is even more marked than in earlier models. The authors show that the negative longwave cloud adjustment inferred in previous studies is primarily caused by a 1.3 W m−2 cloud masking of CO2 forcing. Properly accounting for cloud masking increases net cloud feedback by 0.3 W m−2 K−1, whereas accounting for rapid adjustments reduces by 0.14 W m−2 K−1 the ensemble mean net cloud feedback through a combination of smaller positive cloud amount and altitude feedbacks and larger negative optical depth feedbacks.

ESR and EISCAT observations of the response of the cusp and cleft to IMF orientation changes

We report observations of the cusp/cleft ionosphere made on December 16th 1998 by the EISCAT (European incoherent scatter) VHF radar at Tromso and the EISCAT Svalbard radar (ESR). We compare them with observations of the dayside auroral luminosity, as seen by meridian scanning photometers at Ny Alesund and of HF radar backscatter, as observed by the CUTLASS radar. We study the response to an interval of about one hour when the interplanetary magnetic field (IMF), monitored by the WIND and ACE spacecraft, was southward. The cusp/cleft aurora is shown to correspond to a spatially extended region of elevated electron temperatures in the VHF radar data. Initial conditions were characterised by a northward-directed IMF and cusp/cleft aurora poleward of the ESR. A strong southward turning then occurred, causing an equatorward motion of the cusp/cleft aurora. Within the equatorward expanding, southward-IMF cusp/cleft, the ESR observed structured and elevated plasma densities and ion and electron temperatures. Cleft ion fountain upflows were seen in association with elevated ion temperatures and rapid eastward convection, consistent with the magnetic curvature force on newly opened held lines for the observed negative IMF B-y. Subsequently, the ESR beam remained immediately poleward of the main cusp/cleft and a sequence of poleward-moving auroral transients passed over it. After the last of these, the ESR was in the polar cap and the radar observations were characterised by extremely low ionospheric densities and downward field-aligned flows. The IMF then turned northward again and the auroral oval contracted such that the ESR moved back into the cusp/cleft region. For the poleward-retreating northward-IMF cusp/cleft, the convection flows were slower, upflows were weaker and the electron density and temperature enhancements were less structured. Following the northward turning, the bands of high electron temperature and cusp/cleft aurora bifurcated, consistent with both subsolar and lobe reconnection taking place simultaneously. The present paper describes the large-scale behaviour of the ionosphere during this interval, as observed by a powerful combination of instruments. Two companion papers, by Lockwood et al. (2000) and Thorolfsson et al. (2000), both in this issue, describe the detailed behaviour of the poleward-moving transients observed during the interval of southward B-z, and explain their morphology in the context of previous theoretical work.

The effect of rapid changes in ionospheric flow on velocity vectors deduced from radar beam-swinging experiments

The effects on the horizontal ionospheric velocity vectors deduced from radar beam-swinging experiments, which occur when changes in the flow take place on short time scales compared with the experiment cycle time, are analysed in detail. The further complications which arise in the interpretation of beam-swinging data, due to longitudinal gradients in the flow and to field-aligned flows, are also considered. It is concluded that these effects are unlikely to seriously compromise statistical determinations of the response time of the flow, e.g. to changes in the north-south component of the IMF, such as have been recently reported by Etemadiet al. (1988, Planet. Space Sci.36, 471), using EISCAT ‘Polar’ data.

Response time of the high-latitude dayside ionosphere to sudden changes in the north-south component of the IMF

The time scale of the response of the high-latitude dayside ionospheric flow to changes in the North-South component of the interplanetary magnetic field (IMF) has been investigated by examining the time delays between corresponding sudden changes. Approximately 40 h of simultaneous IMF and ionospheric flow data have been examined, obtained by the AMPTE-UKS and -IRM spacecraft and the EISCAT “Polar” experiment, respectively, in which 20 corresponding sudden changes have been identified. Ten of these changes were associated with southward turnings of the IMF, and 10 with northward turnings. It has been found that the corresponding flow changes occurred simultaneously over the whole of the “Polar” field-of-view, extending more than 2° in invariant latitude, and that the ionospheric response delay following northward turnings is the same as that following southward turnings, though the form of the response is different in the two cases. The shortest response time, 5.5 ± 3.2 min, is found in the early- to mid-afternoon sector, increasing to 9.5 ± 3.0 min in the mid-morning sector, and to 9.5 ± 3.1 min near to dusk. These times represent the delays in the appearance of perturbed flows in the “Polar” field-of-view following the arrival of IMF changes at the subsolar magnetopause. Overall, the results agree very well with those derived by Etemadi et al. (1988, Planet. Space Sci.36, 471) from a general cross-correlation analysis of the IMF Bz and “Polar” beam-swinging vector flow data.

Evidence of resilience to past climate change in Southwest Asia: early farming communities and the 9.2 and 8.2 ka events

Climate change is often cited as a major factor in social change. The so-called 8.2 ka event was one of the most pronounced and abrupt Holocene cold and arid events. The 9.2 ka event was similar, albeit of a smaller magnitude. Both events affected the Northern Hemisphere climate and caused cooling and aridification in Southwest Asia. Yet, the impacts of the 8.2 and 9.2 ka events on early farming communities in this region are not well understood. Current hypotheses for an effect of the 8.2 ka event vary from large-scale site abandonment and migration (including the Neolithisation of Europe) to continuation of occupation and local adaptation, while impacts of the 9.2 ka have not previously been systematically studied. In this paper, we present a thorough assessment of available, quality-checked radiocarbon (14C) dates for sites from Southwest Asia covering the time interval between 9500 and 7500 cal BP, which we interpret in combination with archaeological evidence. In this way, the synchronicity between changes observed in the archaeological record and the rapid climate events is tested. It is shown that there is no evidence for a simultaneous and widespread collapse, large-scale site abandonment, or migration at the time of the events. However, there are indications for local adaptation. We conclude that early farming communities were resilient to the abrupt, severe climate changes at 9250 and 8200 cal BP.

Recent progress in understanding and projecting regional and global mean sea-level change

Considerable progress has been made in understanding the present and future regional and global sea level in the 2 years since the publication of the Fifth Assessment Report (AR5) of the Intergovernmental Panel on Climate Change. Here, we evaluate how the new results affect the AR5’s assessment of (i) historical sea level rise, including attribution of that rise and implications for the sea level budget, (ii) projections of the components and of total global mean sea level (GMSL), and (iii) projections of regional variability and emergence of the anthropogenic signal. In each of these cases, new work largely provides additional evidence in support of the AR5 assessment, providing greater confidence in those findings. Recent analyses confirm the twentieth century sea level rise, with some analyses showing a slightly smaller rate before 1990 and some a slightly larger value than reported in the AR5. There is now more evidence of an acceleration in the rate of rise. Ongoing ocean heat uptake and associated thermal expansion have continued since 2000, and are consistent with ocean thermal expansion reported in the AR5. A significant amount of heat is being stored deeper in the water column, with a larger rate of heat uptake since 2000 compared to the previous decades and with the largest storage in the Southern Ocean. The first formal detection studies for ocean thermal expansion and glacier mass loss since the AR5 have confirmed the AR5 finding of a significant anthropogenic contribution to sea level rise over the last 50 years. New projections of glacier loss from two regions suggest smaller contributions to GMSL rise from these regions than in studies assessed by the AR5; additional regional studies are required to further assess whether there are broader implications of these results. Mass loss from the Greenland Ice Sheet, primarily as a result of increased surface melting, and from the Antarctic Ice Sheet, primarily as a result of increased ice discharge, has accelerated. The largest estimates of acceleration in mass loss from the two ice sheets for 2003–2013 equal or exceed the acceleration of GMSL rise calculated from the satellite altimeter sea level record over the longer period of 1993–2014. However, when increased mass gain in land water storage and parts of East Antarctica, and decreased mass loss from glaciers in Alaska and some other regions are taken into account, the net acceleration in the ocean mass gain is consistent with the satellite altimeter record. New studies suggest that a marine ice sheet instability (MISI) may have been initiated in parts of the West Antarctic Ice Sheet (WAIS), but that it will affect only a limited number of ice streams in the twenty-first century. New projections of mass loss from the Greenland and Antarctic Ice Sheets by 2100, including a contribution from parts of WAIS undergoing unstable retreat, suggest a contribution that falls largely within the likely range (i.e., two thirds probability) of the AR5. These new results increase confidence in the AR5 likely range, indicating that there is a greater probability that sea level rise by 2100 will lie in this range with a corresponding decrease in the likelihood of an additional contribution of several tens of centimeters above the likely range. In view of the comparatively limited state of knowledge and understanding of rapid ice sheet dynamics, we continue to think that it is not yet possible to make reliable quantitative estimates of future GMSL rise outside the likely range. Projections of twenty-first century GMSL rise published since the AR5 depend on results from expert elicitation, but we have low confidence in conclusions based on these approaches. New work on regional projections and emergence of the anthropogenic signal suggests that the two commonly predicted features of future regional sea level change (the increasing tilt across the Antarctic Circumpolar Current and the dipole in the North Atlantic) are related to regional changes in wind stress and surface heat flux. Moreover, it is expected that sea level change in response to anthropogenic forcing, particularly in regions of relatively low unforced variability such as the low-latitude Atlantic, will be detectable over most of the ocean by 2040. The east-west contrast of sea level trends in the Pacific observed since the early 1990s cannot be satisfactorily accounted for by climate models, nor yet definitively attributed either to unforced variability or forced climate change.

Stimulation of phosphatidylinositol hydrolysis, protein kinase C translocation, and mitogen-activated protein kinase activity by bradykinin in rat ventricular myocytes: dissociation from the hypertrophic response.

In ventricular myocytes cultured from neonatal rat hearts, bradykinin (BK), kallidin or BK(1-8) [(Des-Arg9)BK] stimulated PtdinsP2 hydrolysis by 3-4-fold. EC50 values were 6 nM (BK), 2 nM (kallidin), and 14 microM [BK(1-8)]. BK or kallidin stimulated the rapid (less than 30 s) translocation of more than 80% of the novel protein kinase C (PKC) isoforms nPKC-delta and nPKC-epsilon from the soluble to the particulate fraction. EC50 values for nPKC-delta translocation by BK or kallidin were 10 and 2 nM respectively. EC50 values for nPKC-epsilon translocation by BK or kallidin were 2 and 0.6 nM respectively. EC50 values for the translocation of nPKC-delta and nPKC-epsilon by BK(1-8) were more than 5 microM. The classical PKC, cPKC-alpha, and the atypical PKC, nPKC-zeta, did not translocate. BK caused activation and phosphorylation of p42-mitogen-activated protein kinase (MAPK) (maximal at 3-5 min, 30-35% of p42-MAPK phosphorylated). p44-MAPK was similarly activated. EC50 values for p42/p44-MAPK activation by BK were less than 1 nM whereas values for BK(1-8) were more than 10 microM. The order of potency [BK approximately equal to kallidin > BK (1-8)] for the stimulation of PtdInsP2 hydrolysis, nPKC-delta and nPKC-epsilon translocation, and p42/p44-MAPK activities suggests involvement of the B2 BK receptor subtype. In addition, stimulation of all three processes by BK was inhibited by the B2BK receptor-selective antagonist HOE140 but not by the B1-selective antagonist Leu8BK(1-8). Exposure of cells to phorbol 12-myristate 13-acetate for 24 h inhibited subsequent activation of p42/p44-MAPK by BK suggesting participation of nPKC (and possibly cPKC) isoforms in the activation process. Thus, like hypertrophic agents such as endothelin-1 (ET-1) and phenylephrine (PE), BK activates PtdInsP2 hydrolysis, translocates nPKC-delta, and nPKC-epsilon, and activates p42/p44-MAPK. However, in comparison with ET-1 and PE, BK was only weakly hypertrophic as assessed by cell morphology and patterns of gene expression. This difference could not be attributed to dissimilarities between the duration of activation of p42/p44-MAPK by BK or ET-1. Thus activation of these signalling pathways alone may be insufficient to induce a powerful hypertrophic response.

The neurotoxicity of 5-S-cysteinyldopamine is mediated by the early activation of ERK1/2 followed by the subsequent activation of ASK1/JNK1/2 pro-apoptotic signalling

Parkinson's disease is characterized by the progressive and selective loss of dopaminergic neurons in the substantia nigra. It has been postulated that endogenously formed CysDA (5-S-cysteinyldopamine) and its metabolites may be, in part, responsible for this selective neuronal loss, although the mechanisms by which they contribute to such neurotoxicity are not understood. Exposure of neurons in culture to CysDA caused cell injury, apparent 12-48 h post-exposure. A portion of the neuronal death induced by CysDA was preceded by a rapid uptake and intracellular oxidation of CysDA, leading to an acute and transient activation of ERK2 (extracellular-signal-regulated kinase 2) and caspase 8. The oxidation of CysDA also induced the activation of apoptosis signal-regulating kinase 1 via its de-phosphorylation at Ser967, the phosphorylation of JNK (c-Jun N-terminal kinase) and c-Jun (Ser73) as well as the activation of p38, caspase 3, caspase 8, caspase 7 and caspase 9. Concurrently, the inhibition of complex I by the dihydrobenzothiazine DHBT-1 [7-(2-aminoethyl)-3,4-dihydro-5-hydroxy-2H-1,4-benzothiazine-3-carboxylic acid], formed from the intracellular oxidation of CysDA, induces complex I inhibition and the subsequent release of cytochrome c which further potentiates pro-apoptotic mechanisms. Our data suggest a novel comprehensive mechanism for CysDA that may hold relevance for the selective neuronal loss observed in Parkinson's disease.