Greater Reduction in Contralesional Hand Use After Frontoparietal Than Frontal Motor Cortex Lesions in Macaca mulatta.

We previously reported that rhesus monkeys recover spontaneous use of the more impaired (contralesional) hand following neurosurgical lesions to the arm/hand representations of primary motor cortex (M1) and lateral premotor cortex (LPMC) (F2 lesion) when tested for reduced use (RU) in a fine motor task allowing use of either hand. Recovery occurred without constraint of the less impaired hand and with occasional forced use of the more impaired hand, which was the preferred hand for use in fine motor tasks before the lesion. Here, we compared recovery of five F2 lesion cases in the same RU test to recovery after unilateral lesions of M1, LPMC, S1 and anterior portion of parietal cortex (F2P2 lesion - four cases). Average and highest %use of the contralesional hand in the RU task in F2 cases were twice that in F2P2 cases (p < 0.05). Recovery in the RU task was closely associated with volume and percentage of lesion to caudal (new) M1 (M1c) in both F2 and F2P2 lesion cases. One F2P2 case, with the largest M1c lesion and a large rostral somatosensory cortex (S1r) lesion developed severe contralesional hand non-use despite exhibiting some recovery of fine motor function initially. We conclude that the degree of reduced use of the contralesional hand is primarily related to the volume of M1c injury and that severe non-use requires extensive injury to M1c and S1r. Thus, assessing peri-Rolandic injury extent in stroke patients may have prognostic value for predicting susceptibility to RU and non-use in rehabilitation.

Changes in ipsilesional hand motor function differ after unilateral injury to frontal versus frontoparietal cortices in Macaca mulatta.

We tested the hypothesis that injury to frontoparietal sensorimotor areas causes greater initial impairments in performance and poorer recovery of ipsilesional dexterous hand/finger movements than lesions limited to frontal motor areas in rhesus monkeys. Reaching and grasping/manipulation of small targets with the ipsilesional hand were assessed for 6-12 months post-injury using two motor tests. Initial post-lesion motor skill and long-term recovery of motor skill were compared in two groups of monkeys: (1) F2 group-five cases with lesions of arm areas of primary motor cortex (M1) and lateral premotor cortex (LPMC) and (2) F2P2 group-five cases with F2 lesions + lesions of arm areas of primary somatosensory cortex and the anterior portion of area 5. Initial post-lesion reach and manipulation skills were similar to or better than pre-lesion skills in most F2 lesion cases in a difficult fine motor task but worse than pre-lesion skill in most F2P2 lesion cases in all tasks. Subsequently, reaching and manipulation skills improved over the post-lesion period to higher than pre-lesion skills in both groups, but improvements were greater in the F2 lesion group, perhaps due to additional task practice and greater ipsilesional limb use for daily activities. Poorer and slower post-lesion improvement of ipsilesional upper limb motor skill in the F2P2 cases may be due to impaired somatosensory processing. The persistent ipsilesional upper limb motor deficits frequently observed in humans after stroke are probably caused by greater subcortical white and gray matter damage than in the localized surgical injuries studied here.

Terminal organization of the corticospinal projection from the lateral premotor cortex to the cervical enlargement (C5-T1) in rhesus monkey.

High-resolution tract tracing and stereology were used to study the terminal organization of the corticospinal projection (CSP) from the ventral (v) and dorsal (d) regions of the lateral premotor cortex (LPMC) to spinal levels C5-T1. The LPMCv CSP originated from the postarcuate sulcus region, was bilateral, sparse, and primarily targeted the dorsolateral and ventromedial sectors of contralateral lamina VII. The convexity/lateral part of LPMCv did not project below C2. Thus, very little LPMCv corticospinal output reaches the cervical enlargement. In contrast, the LPMCd CSP was 5× more prominent in terminal density. Bilateral terminal labeling occurred in the medial sectors of lamina VII and adjacent lamina VIII, where propriospinal neurons with long-range bilateral axon projections reside. Notably, lamina VIII also harbors axial motoneurons. Contralateral labeling occurred in the lateral sectors of lamina VII and the dorsomedial quadrant of lamina IX, noted for harboring proximal upper limb flexor motoneurons. Segmentally, the CSP to contralateral laminae VII and IX preferentially innervated C5-C7, which supplies shoulder, elbow, and wrist musculature. In contrast, terminations in axial-related lamina VIII were distributed bilaterally throughout all cervical enlargement levels, including C8 and T1. These findings demonstrate the LPMCd CSP is structured to influence axial and proximal upper limb movements, supporting Kuypers conceptual view of the LPMCd CSP being a major component of the medial motor control system. Thus, distal upper extremity control influenced by LPMC, including grasping and manipulation, must occur through indirect neural network connections such as corticocortical, subcortical, or intrinsic spinal circuits.

New Corticopontine Connections in the Primate Brain: Contralateral Projections From the Arm/Hand Area of the Precentral Motor Region.

The ipsilateral corticopontine projection (iCPP) represents a massive descending axon system terminating in the pontine nuclei (PN). In the primate, this projection is well known for its dominant influence on contralateral upper limb movements through the classical cerebrocerebellar circuity system. Although a much weaker contralateral corticopontine projection (cCPP) from motor cortex to the paramedian region has been reported in the non-human primate brain, we provide the first comprehensive description of the cCPP from the lateral motor cortex using high resolution anterograde tract tracing in Macaca mulatta. We found a relatively light cCPP from the hand/arm area of the primary motor cortex (M1), comparatively moderate cCPP from ventrolateral premotor cortex (LPMCv) and a more robust and widespread cCPP from the dorsolateral premotor cortex (LPMCd) that involved all nine contralateral PN. The M1 projection primarily targeted the dorsal pontine region, the LPMCv projection targeted the medial pontine region and LPMCd targeted both regions. These results show the first stage of the primate frontomotor cerebrocerebellar projection is bilateral, and may affect both ipsilateral and contralateral limbs. Clinically, the cCPP originating in the non-injured hemisphere may influence the recovery process of the more affected upper extremity following subtotal unilateral damage to the lateral cortical region. The cCPP may also contribute to the mild impairment of the upper limb contralateral to a unilateral cerebellar injury.

Hand Motor Recovery Following Extensive Frontoparietal Cortical Injury Is Accompanied by Upregulated Corticoreticular Projections in Monkey.

We tested the hypothesis that arm/hand motor recovery after injury of the lateral sensorimotor cortex is associated with upregulation of the corticoreticular projection (CRP) from the supplementary motor cortex (M2) to the gigantocellular reticular nucleus of the medulla (Gi). Three groups of rhesus monkeys of both genders were studied: five controls, four cases with lesions of the arm/hand area of the primary motor cortex (M1) and the lateral premotor cortex (LPMC; F2 lesion group), and five cases with lesions of the arm/hand area of M1, LPMC, S1, and anterior parietal cortex (F2P2 lesion group). CRP strength was assessed using high-resolution anterograde tracers injected into the arm/hand area of M2 and stereology to estimate of the number of synaptic boutons in the Gi. M2 projected bilaterally to the Gi, primarily targeting the medial Gi subsector and, to a lesser extent, lateral, dorsal, and ventral subsectors. Total CRP bouton numbers were similar in controls and F2 lesion cases but F2P2 lesion cases had twice as many boutons as the other two groups (p = 0.0002). Recovery of reaching and fine hand/digit function was strongly correlated with estimated numbers of CRP boutons in the F2P2 lesion cases. Because we previously showed that F2P2 lesion cases experience decreased strength of the M2 corticospinal projection (CSP), whereas F2 lesion monkeys experienced increased strength of the M2 CSP, these results suggest one mechanism underlying arm/hand motor recovery after F2P2 injury is upregulation of the M2 CRP. This M2-CRP response may influence an important reticulospinal tract contribution to upper-limb motor recovery following frontoparietal injury.SIGNIFICANCE STATEMENT We previously showed that after brain injury affecting the lateral motor cortex controlling arm/hand motor function, recovery is variable and closely associated with increased strength of corticospinal projection (CSP) from an uninjured medial cortical motor area. Hand motor recovery also varies after brain injury affecting the lateral sensorimotor cortex, but medial motor cortex CSP strength decreases and cannot account for recovery. Here we observed that motor recovery following sensorimotor cortex injury is closely associated with increased strength of the descending projection from an uninjured medial cortical motor area to a brainstem reticular nucleus involved in control of arm/hand function, suggesting an enhanced corticoreticular projection may compensate for injury to the sensorimotor cortex to enable recovery of arm/hand motor function.

Chronic vagal nerve stimulation prevents high-salt diet-induced endothelial dysfunction and aortic stiffening in stroke-prone spontaneously hypertensive rats.

Parasympathetic activity is often reduced in hypertension and can elicit anti-inflammatory mechanisms. Thus we hypothesized that chronic vagal nerve stimulation (VNS) may alleviate cardiovascular end-organ damage in stroke-prone spontaneously hypertensive rats. Vagal nerve stimulators were implanted, a high-salt diet initiated, and the stimulators turned on (VNS, n = 10) or left off (sham, n = 14) for 4 wk. Arterial pressure increased equally in both groups. After 4 wk, endothelial function, assessed by in vivo imaging of the long posterior ciliary artery (LPCA) after stimulation (pilocarpine) and inhibition (N(ω)-nitro-l-arginine methyl ester) of endothelial nitric oxide synthase (eNOS), had significantly declined (-2.3 ± 1.2 µm, P < 0.05) in sham, but was maintained (-0.7 ± 0.8 µm, nonsignificant) in VNS. Furthermore, aortic eNOS activation (phosphorylated to total eNOS protein content ratio) was greater in VNS (0.83 ± 0.07) than in sham (0.47 ± 0.08, P < 0.05). After only 3 wk, ultrasound imaging of the aorta demonstrated decreased aortic strain (-9.7 ± 2.2%, P < 0.05) and distensibility (-2.39 ± 0.49 1,000/mmHg, P < 0.05) and increased pulse-wave velocity (+2.4 ± 0.7 m/s, P < 0.05) in sham but not in VNS (-3.8 ± 3.8%, -0.70 ± 1.4 1,000/mmHg, and +0.1 ± 0.7 m/s, all nonsignificant). Interleukin (IL)-6 serum concentrations tended to be higher in VNS than in sham (34.3 ± 8.3 vs. 16.1 ± 4.6 pg/ml, P = 0.06), and positive correlations were found between NO-dependent relaxation of the LPCA and serum levels of IL-6 (r = +0.70, P < 0.05) and IL-10 (r = +0.56, P < 0.05) and between aortic eNOS activation and IL-10 (r = +0.48, P < 0.05). In conclusion, chronic VNS prevents hypertension-induced endothelial dysfunction and aortic stiffening in an animal model of severe hypertension. We speculate that anti-inflammatory mechanisms may contribute to these effects.

Sensorimotor cortex injury effects on recovery of contralesional dexterous movements in Macaca mulatta.

The effects of primary somatosensory cortex (S1) injury on recovery of contralateral upper limb reaching and grasping were studied by comparing the consequences of isolated lesions to the arm/hand region of primary motor cortex (M1) and lateral premotor cortex (LPMC) to lesions of these same areas plus anterior parietal cortex (S1 and rostral area PE). We used multiple linear regression to assess the effects of gray and white matter lesion volumes on deficits in reaching and fine motor performance during the first month after the lesion, and during recovery of function over 3, 6 and 12months post-injury in 13 monkeys. Subjects with frontoparietal lesions exhibited larger deficits and poorer recovery as predicted, including one subject with extensive peri-Rolandic injury developing learned nonuse after showing signs of recovery. Regression analyses showed that total white matter lesion volume was strongly associated with initial post-lesion deficits in motor performance and with recovery of skill in reaching and manipulation. Multiple regression analyses using percent damage to caudal M1 (M1c), rostral S1 (S1r), LPMC and area PE as predictor variables showed that S1r lesion volumes were closely related to delayed post-lesion recovery of upper limb function, as well as lower skill level of recovery. In contrast, M1c lesion volume was related primarily to initial post-lesion deficits in hand motor performance. Overall, these findings demonstrate that frontoparietal injury impairs hand motor function more so than frontal motor injury alone, and results in slower and poorer recovery than lesions limited to frontal motor cortex.

Recovery of precision grasping after motor cortex lesion does not require forced use of the impaired hand in Macaca mulatta.

We investigated recovery of precision grasping of small objects between the index finger and thumb of the impaired hand without forced use after surgically placed lesions to the hand/arm areas of M1 and M1 + lateral premotor cortex in two monkeys. The unilateral lesions were contralateral to the monkey's preferred hand, which was established in prelesion testing as the hand used most often to acquire raisins in a foraging board (FB) task in which the monkey was free to use either hand to acquire treats. The lesions initially produced a clear paresis of the contralesional hand and use of only the ipsilesional hand to acquire raisins in the FB task. However, beginning about 3 weeks after the lesion both monkeys spontaneously began using the impaired contralesional hand in the FB task and increased use of that hand over the next few tests. Moreover, the monkeys clearly used precision grasp to acquire the raisins in a similar manner to prelesion performances, although grasp durations were longer. Although the monkeys used the contralesional hand more often than the ipsilesional hand in some postlesion testing sessions, they did not recover to use the hand as often as in prelesion testing when the preferred hand was used almost exclusively. These findings suggest that recovery of fine hand/digit motor function after localized damage to the lateral frontal motor areas in rhesus monkeys does not require forced use of the impaired hand.

Laterality affects spontaneous recovery of contralateral hand motor function following motor cortex injury in rhesus monkeys.

The purpose of this study was to test whether brain laterality influences spontaneous recovery of hand motor function after controlled brain injuries to arm areas of M1 and lateral premotor cortex (LPMC) of the hemisphere contralateral to the preferred hand in rhesus monkeys. We hypothesized that monkeys with stronger hand preference would exhibit poorer recovery of skilled hand use after such brain injury. Degree of handedness was assessed using a standard dexterity board task in which subjects could use either hand to retrieve small food pellets. Fine hand/digit motor function was assessed using a modified dexterity board before and after the M1 and LPMC lesions in ten monkeys. We found a strong negative relationship between the degree of handedness and the recovery of manipulation skill, demonstrating that higher hand preference was associated with poorer recovery of hand fine motor function. We also observed that monkeys with larger lesions within M1 and LPMC had greater initial impairment of manipulation and poorer recovery of reaching skill. We conclude that monkeys with a stronger hand preference are likely to show poorer recovery of contralesional hand fine motor skill after isolated brain lesions affecting the lateral frontal motor areas. These data may be extended to suggest that humans who exhibit weak hand dominance, and perhaps individuals who use both hands for fine motor tasks, may have a more favorable potential for recovery after a unilateral stroke or brain injury affecting the lateral cortical motor areas than individuals with a high degree of hand dominance.

Volumetric effects of motor cortex injury on recovery of ipsilesional dexterous movements.

Damage to the motor cortex of one hemisphere has classically been associated with contralateral upper limb paresis, but recent patient studies have identified deficits in both upper limbs. In non-human primates, we tested the hypothesis that the severity of ipsilesional upper limb motor impairment in the early post-injury phase depends on the volume of gray and white matter damage of the motor areas of the frontal lobe. We also postulated that substantial recovery would accompany minimal task practice and that ipsilesional limb recovery would be correlated with recovery of the contralesional limb. Gross (reaching) and fine hand motor functions were assessed for 3-12 months post-injury using two motor tests. Volumes of white and gray matter lesions were assessed using quantitative histology. Early changes in post-lesion motor performance were inversely correlated with white matter lesion volume indicating that larger lesions produced greater decreases in ipsilesional hand movement control. All monkeys showed improvements in ipsilesional hand motor skill during the post-lesion period, with reaching skill improvements being positively correlated with total lesion volume indicating that larger lesions were associated with greater ipsilesional motor skill recovery. We suggest that reduced trans-callosal inhibition from the lesioned hemisphere may play a role in the observed skill improvements. Our findings show that significant ipsilesional hand motor recovery is likely to accompany injury limited to frontal motor areas. In humans, more pronounced ipsilesional motor deficits that invariably develop after stroke may, in part, be a consequence of more extensive subcortical white and gray matter damage.

Noninvasive assessment of vascular structure and function in conscious rats based on in vivo imaging of the albino iris.

Experimental techniques allowing longitudinal studies of vascular disease progression or treatment effects are not readily available for most animal models. Thus, most existing studies are destined to either study individual time points or use large cohorts of animals. Here we describe a noninvasive technique for studying vascular disease that is based on in vivo imaging of the long posterior ciliary artery (LPCA) in the iris of albino rats. Using a slit-lamp biomicroscope, images of the LPCA were taken weekly in conscious normotensive Wistar Kyoto rats (WKY, n = 10) and spontaneously hypertensive rats (SHR, n = 10) for 10 wk. Using imaging software, we found that lumen diameter was significantly smaller and the wall-to-lumen (W/L) ratio larger in SHR than in WKY. Wall thickness was not different. Blood pressure correlated with the W/L ratio. Histology of the abdominal aorta also revealed a smaller lumen diameter and greater W/L ratio in SHR compared with WKY. Corneal application of the muscarinic receptor agonist pilocarpine elicited a dose-dependent vasodilation of the LPCA that could be antagonized by inhibition of nitric oxide synthase, suggesting that the pilocarpine response is mainly mediated by endothelium-derived nitric oxide. Consistent with endothelial dysfunction in SHR, pilocarpine-induced vasodilation was greater in WKY rats than in SHR. These findings indicate that in vivo imaging of the LPCA allows assessment of several structural and functional vascular parameters in conscious rats and that the LPCA responds to disease insults and pharmacologic treatments in a fashion that will make it a useful model for further studies.

Minimal forced use without constraint stimulates spontaneous use of the impaired upper extremity following motor cortex injury.

The purpose of this study was to determine if recovery of neurologically impaired hand function following isolated motor cortex injury would occur without constraint of the non-impaired limb, and without daily forced use of the impaired limb. Nine monkeys (Macaca mulatta) received neurosurgical lesions of various extents to arm representations of motor cortex in the hemisphere contralateral to the preferred hand. After the lesion, no physical constraints were placed on the ipsilesional arm/hand and motor testing was carried out weekly with a maximum of 40 attempts in two fine motor tasks that required use of the contralesional hand for successful food acquisition. These motor tests were the only "forced use" of the contralesional hand. We also tested regularly for spontaneous use of the contralesional hand in a fine motor task in which either hand could be used for successful performance. This minimal intervention was sufficient to induce recovery of the contralesional hand to such a functional level that eight of the monkeys chose to use that hand on some trials when either hand could be used. Percentage use of the contralesional hand (in the task when either hand could be used) varied considerably among monkeys and was not related to lesion volume or recovery of motor skill. These data demonstrate a remarkable capacity for recovery of spontaneous use of the impaired hand following localized frontal lobe lesions. Clinically, these observations underscore the importance of therapeutic intervention to inhibit the induction of the learned nonuse phenomenon after neurological injury.

Selective long-term reorganization of the corticospinal projection from the supplementary motor cortex following recovery from lateral motor cortex injury.

Brain injury affecting the frontal motor cortex or its descending axons often causes contralateral upper extremity paresis. Although recovery is variable, the underlying mechanisms supporting favorable motor recovery remain unclear. Because the medial wall of the cerebral hemisphere is often spared following brain injury and recent functional neuroimaging studies in patients indicate a potential role for this brain region in the recovery process, we investigated the long-term effects of isolated lateral frontal motor cortical injury on the corticospinal projection (CSP) from intact, ipsilesional supplementary motor cortex (M2). After injury to the arm region of the primary motor (M1) and lateral premotor (LPMC) cortices, upper extremity recovery is accompanied by terminal axon plasticity in the contralateral CSP but not the ipsilateral CSP from M2. Furthermore, significant contralateral plasticity occurs only in lamina VII and dorsally within lamina IX. Thus, selective intraspinal sprouting transpires in regions containing interneurons, flexor-related motor neurons, and motor neurons supplying intrinsic hand muscles, which all play important roles in mediating reaching and digit movements. After recovery, subsequent injury of M2 leads to reemergence of hand motor deficits. Considering the importance of the CSP in humans and the common occurrence of lateral frontal cortex injury, these findings suggest that spared supplementary motor cortex may serve as an important therapeutic target that should be considered when designing acute and long-term postinjury patient intervention strategies aimed to enhance the motor recovery process following lateral cortical trauma.

Volumetric effects of motor cortex injury on recovery of dexterous movements.

Due to the heterogeneous nature of most brain injuries, the contributions of gray and white matter involvement to motor deficits and recovery potential remain obscure. We tested the hypothesis that duration of hand motor impairment and recovery of skilled arm and hand motor function depends on the volume of gray and white matter damage of the frontal lobe. Lesions of the primary motor cortex (M1), M1 + lateral premotor cortex (LPMC), M1 + LPMC + supplementary motor cortex (M2) or multifocal lesions affecting motor areas and medial prefrontal cortex were evaluated in rhesus monkeys. Fine hand motor function was quantitatively assessed pre-lesion and for 3-12 months post-lesion using two motor tests. White and gray matter lesion volumes were determined using histological and quantitative methods. Regression analyses showed that duration of fine hand motor impairment was strongly correlated (R(2)>0.8) with the volume of gray and white matter lesions, with white matter lesion volume being the primary predictor of impairment duration. Level of recovery of fine hand motor skill was also well correlated (R(2)>0.5) with gray and white matter lesion volume. In some monkeys post-lesion skill exceeded pre-lesion skill in one or both motor tasks demonstrating that continued post-injury task practice can improve motor performance after localized loss of frontal motor cortex. These findings will assist in interpreting acute motor deficits, predicting the time course and expected level of functional recovery, and designing therapeutic strategies in patients with localized frontal lobe injury or neurosurgical resection.

Very low frequency blood pressure variability is modulated by myogenic vascular function and is reduced in stroke-prone rats.

BACKGROUND: Cerebrovascular myogenic function, which protects the brain from hemorrhagic stroke, is impaired in stroke-prone spontaneously hypertensive rats. Furthermore, myogenic function contributes to very low frequency blood pressure variability and dynamic autoregulation of cerebral blood flow is most effective at very low frequency in rats. Therefore, we hypothesized that very low frequency blood pressure variability is reduced in stroke-prone spontaneously hypertensive rats compared with stroke-resistant spontaneously hypertensive rats. In addition, we investigated if myogenic function also contributes to very low frequency blood pressure variability in conscious dogs. METHODS: In 8-week-old normotensive Wistar-Kyoto rats, 8-week-old and 15-week-old stroke-prone spontaneously hypertensive rats and stroke-resistant spontaneously hypertensive rats, and dogs, blood pressure variability was studied during control conditions, inhibition of myogenic function (nifedipine) and hypotension induced by sodium nitroprusside. In dogs, transfer function analysis between blood pressure and total peripheral resistance was performed to study the contribution of myogenic function to blood pressure variability. RESULTS: Inhibition of myogenic function, but not hypotension induced by sodium nitroprusside, significantly reduced very low frequency variability of systolic blood pressure (rats: 0.02-0.2 Hz; dogs: 0.02-0.075 Hz) in conscious rats and dogs. In dogs, the gain of the transfer function was high (0.28 +/- 0.04 min/l) in the very low frequency band and was decreased to 0.11 +/- 0.01 min/l (P < 0.05) by nifedipine but not by sodium nitroprusside (0.26 +/- 0.02 min/l). Very low frequency blood pressure variability was significantly smaller in stroke-prone spontaneously hypertensive rats than in stroke-resistant spontaneously hypertensive rats (8 weeks of age: 7.8 +/- 1.1 vs. 13.1 +/- 2.2 mmHg; P < 0.05; 15 weeks of age: 7.1 +/- 1.2 vs. 16.5 +/- 3.6 mmHg; P < 0.05). CONCLUSION: Myogenic function affects very low frequency blood pressure variability in conscious rats and dogs. The smaller very low frequency blood pressure variability in stroke-prone spontaneously hypertensive rats compared with stroke-resistant spontaneously hypertensive rats suggests that impaired cerebrovascular myogenic function is reflected in reduced very low frequency blood pressure variability.

Measurement of reaching kinematics and prehensile dexterity in nonhuman primates.

A modified "Klüver" or dexterity board was developed to assess fine control of hand and digit movements by nonhuman primates during the acquisition of small food pellets from wells of different diameter. The primary advantages of the new device over those used previously include standardized positioning of target food pellets and controlled testing of each hand without the need for restraints, thereby allowing the monkey to move freely about the cage. Three-dimensional video analysis of hand motion was used to provide measures of reaching accuracy and grip aperture, as well as temporal measures of reach duration and food-pellet manipulation. We also present a validated performance score based on these measures, which serves as an indicator of successful food-pellet retrieval. Tests in three monkeys show that the performance score is an effective measure with which to study fine motor control associated with learning and handedness. We also show that the device and performance scores are effective for differentiating the effects of localized injury to motor areas of the cerebral cortex.

Frequency response characteristics of cerebral blood flow autoregulation in rats.

Transfer function analysis of blood pressure and cerebral blood flow in humans demonstrated that cerebrovascular autoregulation operates most effectively for slow fluctuations in perfusion pressure, not exceeding a frequency of approximately 0.15 Hz. No information on the dynamic properties of cerebrovascular autoregulation is available in rats. Therefore, we tested the hypothesis that cerebrovascular autoregulation in rats is also most effective for slow fluctuations in perfusion pressure below 0.15 Hz. Normotensive Wistar-Kyoto rats (n = 10) were instrumented with catheters in the left common carotid artery and jugular vein and flow probes around the right internal carotid artery. During isoflurane anesthesia, fluctuations in cerebral perfusion pressure were elicited by periodically occluding the abdominal aorta at eight frequencies ranging from 0.008 Hz to 0.5 Hz. The protocol was repeated during inhibition of myogenic vascular function (nifedipine, 0.25 mg/kg body wt iv). Increases in cerebral perfusion pressure elicited initial increases in cerebrovascular conductance and decreases in resistance. At low occlusion frequencies (<0.1 Hz), these initial responses were followed by decreases in conductance and increases in resistance that were abolished by nifedipine. At occlusion frequencies of 0.1 Hz and above, the gains of the transfer functions between pressure and blood flow and between pressure and resistance were equally high in the control and nifedipine trial. At occlusion frequencies below 0.1 Hz, the gains of the transfer functions decreased twice as much under control conditions than during nifedipine application. We conclude that dynamic autoregulation of cerebral blood flow is restricted to very low frequencies (<0.1 Hz) in rats.

Very low-frequency blood pressure variability depends on voltage-gated L-type Ca2+ channels in conscious rats.

The mechanisms generating high- frequency (HF) and low-frequency (LF) blood pressure variability (BPV) are reasonably well understood. However, little is known about the origin of very low-frequency (VLF) BPV. We tested the hypothesis that VLF BPV is generated by L-type Ca(2+) channel-dependent mechanisms. In conscious rats, arterial blood pressure was recorded during control conditions (n = 8) and ganglionic blockade (n = 7) while increasing doses (0.01-5.0 mg.100 micro l(-1).h(-1)) of the L-type Ca(2+) channel blocker nifedipine were infused intravenously. VLF (0.02-0.2 Hz), LF (0.2-0.6 Hz), and HF (0.6-3.0 Hz) BPV were assessed by spectral analysis of systolic blood pressure. During control conditions, nifedipine caused dose-dependent declines in VLF and LF BPV, whereas HF BPV was not affected. At the highest dose of nifedipine, VLF BPV was reduced by 86% compared with baseline, indicating that VLF BPV is largely mediated by L-type Ca(2+) channel-dependent mechanisms. VLF BPV appeared to be relatively more dependent on L-type Ca(2+) channels than LF BPV because lower doses of nifedipine were required to significantly reduce VLF BPV than to reduce LF BPV. Ganglionic blockade markedly reduced VLF and LF BPV and abolished the nifedipine-induced dose-dependent declines in VLF and LF BPV, suggesting that VLF and LF BPV require sympathetic activity to be evident. In conclusion, VLF BPV is largely mediated by L-type Ca(2+) channel-dependent mechanisms. We speculate that VLF BPV is generated by myogenic vascular responses to spontaneously occurring perturbations of blood pressure. Other factors, such as sympathetic nervous system activity, may elicit a permissive effect on VLF BPV by increasing vascular myogenic responsiveness.